Methods of generating antibodies

ABSTRACT

The invention describes a method of generating antibodies to a mixture of peptidogenic proteins wherein the peptidogenic protein has altered conformational dynamics as compared to a starting protein and wherein the peptidogenic protein has a similar conformation to the starting protein. The peptidogenic proteins can be used to induce an immune response, which can lead to the generation of antibodies and/or can be used to vaccinate a mammal.

CROSS-REFERENCE TO RELATED APPLICATIONS

This Application claims priority to U.S. Provisional Application62/207,022, filed Aug. 19, 2015, which is incorporated herein byreference in its entirety.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted in ASCII format via EFS-Web and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Aug. 16, 2016, isnamed Combined_SA_01_PCT_ST25_V2.txt and is 10,883,263 bytes in size.

INTRODUCTION

Methods for making antibodies have been around for over 100 years andare routinely used by the skilled artisan. See, for example, Morrison etal., Science 229:1202 (1985); Oi et al., BioTechniques 4:214 (1986);Cabilly et al., U.S. Pat. No. 4,816,567; Taniguchi et al., EP 171496;Morrison et al., EP 173494; Neuberger et al., WO 8601533; Robinson etal., WO 8702671; Boulianne et al., Nature 312:643 (1984); Neuberger etal., Nature 314:268 (1985). Improved methods for generating antibodieshave extended these initial methods and have been used to generate manyof the therapeutic antibodies now being sold commercially. For example,technologies such as phage display and transgenic mice, that is, micecontaining the human immunoglobulin genes, have been used to generatefully human antibodies. However, certain antigens continue to challengea researcher's ability to raise antibodies even when using the mostcurrent techniques.

To induce a cell-mediated immune response within the human body, foreignproteins are broken down into smaller peptides, usually between 8-24amino acids in length, and are bound to MHC molecules, for display onthe surface of antigen presenting cells. The MHC-bound peptides arepresented to T-cells to trigger a cell mediated immune response.

The three-dimensional (3D) structure of proteins has been implicated asa factor in proteolytic processing and presentation of epitopes (see,Carmicle et al., Molecular Immunology (2007) vol. 44: 1159-1168).Moreover, Ohkuri et al. (see, Okhuri et al., J. Immunol., (2010), vol.185: 4199-4205) agreed that conformational stability of a protein is animmunologically dominant factor. However, there is no consensusregarding exactly how the 3D structure affects the immune response.

Delamarre et al. (see, Delamarre et al., JEM, (2006), vol 203:2049-2055) found that less digestible forms of proteins that were lesssusceptible to digestion via lysosomal proteolysis were moreimmunogenic, and therefore, concluded that increasing protein stabilityimproved the immune response. For example, Delamarre et al. showed thatthe immunogenicity of protein antigens can be improved by reducingsusceptibility to proteolysis. Similarly, Mirano-Bascos et al. (see,Mirano-Bascos et al., J. of Virology, (2010), vol. 84: 3303-3311)mutated cysteine residues to prevent each of three disulfide bonds fromforming, and determined that the CD4+ T-cell response was broadlyreduced for all three variants. Mirano-Bascos et al. similarly concludedthat global destabilization of the 3-D structure of a protein reducedantigenic presentation and led to a suppressed immune response. In otherstudies, such as for example, Nguyen et al., Vaccine, (2015), vol. 33:2887-2896, outer domain disulfide bonds were deleted with theexpectation that such deletions would improve antigenic presentation.Instead, a typical pattern of epitope dominance was observed and theauthors concluded that it may not be possible to generate asubstantially stronger immune response.

Other groups similarly conclude that protein stabilization is needed foran immune response. For example, Deressa et al., (see, Deressa et al.,PLOS, (2014), vol. 9: 1-12) concluded that even minor modifications inthe amino acid sequence of an antigen caused fundamental quantitativeand qualitative changes in the immune response. Likewise, Porta et al.(see, Porta et al., PLOS, (2013), vol. 9: 1-8) reported that stabilityis needed for inducing an immune response. Other groups such as Thomas(see, Thomas et al., Human Vaccines & Immunotherapeutics, (2013), vol.9:744-752) similarly concluded that increasing thermal stability forpeptides elicited a better immune response.

In contrast, other groups such as So (see, So et al., Immunology,(2001), vol. 104: 259-268) report conflicting results. So et al.investigated the effect of crosslinking (e.g., removing cross-links andadding crosslinks) on the magnitude of in vivo T-cell responses andfound that removing such crosslinks led to better antigen processing andan improved immune response. Similarly, Thai et al., J. Biol. Chem.(2004) vol. 279: 50257-50266) reported mutating surface accessibleresidues to decrease stability and increase conformational dynamics toincrease the immunogenicity of the protein antigen. Thai et al. is alsodirected towards administration of single antigens.

There is no consensus on whether removing or adding crosslinks improvesor inhibits antigen processing. Accordingly, it is unclear in the art asto whether increasing or decreasing protein stability would lead to animproved immune response comprising a broad, diverse array ofantibodies.

Thus, there continues to be a need to develop new and improved methodsof generating antibodies which can provide a different and broaderrepertoire of antibodies than previously obtained.

SUMMARY OF THE INVENTION

This summary is provided to introduce a selection of concepts in asimplified form that are further described below in the DetailedDescription. This summary is not intended to identify key features oressential features of the claimed subject matter, nor is it intended tobe used as an aid in determining the scope of the claimed subject.

As described herein, the invention is directed towards a method oftriggering an immune response wherein said method comprises designing amixture of peptidogenic proteins derived from a starting protein,wherein the peptidogenic proteins have altered conformational dynamicsas compared to the starting protein and wherein the peptidogenicproteins are similar in conformation to the starting protein,introducing the peptidogenic proteins to an animal and generating animmune response. The peptidogenic proteins can be introduced into theanimals directly (by, for instance, inoculation or immunization) or canbe expressed in vivo by polynucleotides that have been introduced intothe animal and which encode the peptidogenic proteins. Upon expressionof these peptidogenic proteins, the immune response is triggered togenerate antibodies both to the peptidogenic proteins and to theoriginal starting protein.

In preferred embodiments, the conformational dynamics of a startingprotein are preferably altered by altering the thermodynamic stabilityof the starting protein. In further preferred embodiments, theconformational dynamics of the starting protein are altered by replacingat least one non-surface amino acid residue of a starting protein tomodify the peptidogenicity of the protein. Methods of alteringconformational dynamics include, but are not limited to, examining amodel of the 3-D structure (experimental or predicted based on homology)of the starting protein, identifying non-surface amino acid residues ofthe starting protein and replacing at least one non-surface amino acidresidue in the starting protein to generate the peptidogenic protein,and/or by comparing the pattern of conserved amino acid homology acrossproteins orthologous to the starting protein from different species toprovisionally identify non-surface amino acid residues of the startingprotein (e.g., conserved hydrophobic residues) and replacing at leastone non-surface amino acid residue in the starting protein to generatethe peptidogenic protein. Other methods of predicting or empiricallydiscovering non-surface (i.e., buried) amino acid residues can also beused. These methods also include using bioinformatics tools that predictsecondary structures and/or identify disordered regions of a startingprotein to identify at least one non-surface amino acid residue withinthese structures or ordered regions for replacement, and replacing theat least one non-surface amino acid residue to generate the peptidogenicprotein (see, e.g., Cheng et al., Nucleic Acids Res (2005) 33:W72-6;Huang et al. (2014), DisMeta: A Meta Server for Construct Design andOptimization In Chen editor, Structural Genomics, Humana Press pp.3-16). In some embodiments, substitutions in disordered regions areavoided. For example, disorder predictors could be used to identifyordered/structured regions in order to select ordered regions in whichto make mutations (Id.). Still other methods include using biochemicalexperiments to identify core residues, such as through alanine scanningof hydrophobic residues or comparable methods, to identify at least onenon-surface amino acid residue within these structures or regions forreplacement, and replacing the at least one non-surface amino acidresidue to generate the peptidogenic protein. Accordingly, in someembodiments, residues for replacement can be identified based on knownstructures, and in other embodiments, residues for replacement can beidentified based on conserved hydrophobic residues.

In preferred embodiments a non-surface amino acid residue is replacedwith a smaller amino acid residue. In further preferred embodiments, thesmaller amino acid is an alanine or glycine. In other preferredembodiments, at least 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids arereplaced in the starting protein. In still other preferred embodiments,at least 10 amino acids, at least 20 amino acids, at least 30 aminoacids, at least 40 amino acids, or at least 50 amino acids are replacedin the starting protein. In still other preferred embodiments, multipleamino acid replacements are distributed across a mixture of proteins.For example, in one embodiment, to mutate 10 different residues, thestarting protein is mutated 10 different times to generate 10 differentpeptidogenic proteins, each with a single amino acid replacement. Eachof the ten proteins are mixed together to inoculate the animal. In somecases, wild type starting protein, i.e. the protein with no mutations,is part of the mixture. In further preferred embodiments, at least onedisulfide bond is eliminated in the starting protein, such as, forexample, replacing the cysteines with alanines, serines, and/orglycines, etc. In further preferred embodiments, both cysteines involvedin the formation of the at least one disulfide bond in the startingprotein are replaced with alanines, serines, and/or glycines, orpreferably with alanines or glycines, etc. In further preferredembodiments, the conformational dynamics of the starting protein isaltered by replacing (a) at least one threonine with a valine, alanine,glycine or serine; or (b) at least one cysteine with alanine, valine,glycine, serine or threonine; or (c) at least one valine with alanine,glycine, leucine or isoleucine; or (d) at least one leucine withalanine, valine, glycine, or isoleucine; or (e) at least one isoleucinewith alanine, valine, leucine, or glycine; or (f) at least one proline,methionine, phenylalanine, tyrosine, or tryptophan with alanine, valine,leucine, isoleucine, or glycine; or (g) at least one aspartic acid orasparagine with glycine, serine, threonine, alanine, valine, leucine, orisoleucine; or (h) at least one glutamic acid or glutamine with asparticacid, asparagine, glycine, serine, threonine, alanine, valine, leucine,or isoleucine; or (i) at least one lysine with arginine, histidine,glycine, serine, threonine, alanine, valine, methionine, leucine, orisoleucine; or (j) at least one arginine with lysine, histidine,glycine, serine, threonine, alanine, valine, methionine, leucine, orisoleucine; or (k) at least one histidine with lysine, arginine,glycine, serine, threonine, alanine, valine, glutamine, asparagine,leucine, or isoleucine; or (l) at least one alanine with a glycine; or(m) at least one residue with a non-natural amino acid; and/or (n) anyof the above combinations.

In still further preferred embodiments, the conformational dynamics ofthe starting protein is altered by replacing: (a) at least onetryptophan with tyrosine, phenylalanine, methionine, histidine,isoleucine, leucine, valine, alanine or glycine; or (b) at least onetyrosine with phenylalanine, methionine, histidine, isoleucine, leucine,valine, alanine or glycine; or (c) at least one phenylalanine withtyrosine, methionine, histidine, isoleucine, leucine, valine, alanine orglycine; or (d) at least one proline with methionine, leucine,isoleucine, valine, alanine, or glycine; or (e) at least one histidinewith phenylalanine, tyrosine, methionine, isoleucine, leucine, valine,alanine, glycine, lysine, arginine, serine, threonine, asparagine, orglutamine; or (f) at least one methionine with isoleucine, leucine,valine, alanine or glycine; or (g) at least one isoleucine with leucine,valine, alanine or glycine; or (h) at least one leucine with isoleucine,valine, alanine or glycine; or (i) at least one valine with alanine,glycine, leucine, or isoleucine; or (j) at least one cysteine withalanine, valine, glycine, serine or threonine; or (k) at least oneaspartic acid with glutamic acid, glutamine, asparagine, glycine,serine, threonine, alanine, valine, leucine, or isoleucine; or (l) atleast one glutamic acid with aspartic acid, glutamine, asparagine,glycine, serine, threonine, alanine, valine, leucine, or isoleucine; or(m) at least one alanine with a glycine or proline; or (n) at least oneserine with alanine or glycine; or (o) at least one glycine with alanineor proline; or (p) at least one lysine with arginine, histidine,glycine, serine, threonine, alanine, valine, methionine, leucine orisoleucine; or (q) at least one asparagine with glycine, alanine,serine, threonine, valine, leucine, isoleucine, glutamine, aspartic acidor glutamic acid; or (r) at least one glutamine with glycine, alanine,serine, threonine, valine, leucine, isoleucine, glutamine, asparticacid, glutamic acid, or histidine; or (s) at least one arginine withlysine, histidine, glycine, serine, threonine, alanine valine,methionine, leucine, or isoleucine; or (t) at least one threonine withvaline, alanine, glycine or serine; or (u) a hydrophobic residue with asmaller, similar hydrophobic residue; or (v) at least one residue with anon-natural amino acid; or (w) any of the above combinations. Acombinatorial approach may be used to determine optimal substitutions toincrease peptidogenicity.

In preferred embodiments, the change in conformational dynamics of thepeptidogenic protein is measured by a change in melting temperature ascompared to the starting protein and/or by measuring a change in Gibbsfree energy of stabilization. Preferred methods of measuring Gibbs freeenergy include, but are not limited to, denaturant modulated equilibriumunfolding. Preferred denaturants are urea and/or guanidiniumhydrochloride. Alternatively, changes in conformational dynamics can beassayed by detecting a change in a proteolytic sensitivity assay, suchas, for example, by measuring digestion with cathepsins and/or otherproteases and then analyzing the mixture by mass spectrometry (MS) orsodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE).

In preferred embodiments, determining whether peptidogenic proteins havea similar conformation to the starting protein can be measured by across-reacting antibody that binds to a 3D conformational epitope (oftena discontinuous epitope) on both the peptidogenic proteins and thestarting protein. Methods for measuring antibody binding include, butare not limited to an immunoprecipitation assay, surface plasmaresonance, isothermal titration calorimetry, oblique-incidencereflective difference (OI-RD), western blots, radioimmunoassays, ELISA(enzyme linked immunosorbent assay), “sandwich” immunoassays, geldiffusion precipitin reactions, immunodiffusion assays, agglutinationassays, complement-fixation assays, immunoradiometric assays,fluorescent immunoassays, and/or protein A immunoassays.

In further preferred embodiments, a test for measuring cross-reactivityis by a binding assay. In further preferred embodiment, the antibodybinding (including a cross-reacting antibody) to a peptidogenic proteinhas a dissociation constant (KD) of less than or equal to 10⁻⁹M, of lessthan or equal to 10⁻⁸M, less than or equal to 10⁻⁷M, and/or less than orequal to 10⁻⁶M.

In preferred embodiments, the starting protein is selected from anenvelope glycoprotein of the human immunodeficiency virus (HIV), HIVgp120, HIV gp41, HIV gp160, an ebola antigen, a hepatitis C virus (HCV)antigen, a hepatitis B virus (HBV) antigen, a Middle Eastern RespiratorySyndrome coronavirus (MERS-CoV) antigen, a Zika virus antigen, aninfluenza virus antigen, a viral antigen, a malaria antigen, a bacterialantigen, a parasitic antigen, an allergen, a venom, a toxin, or atumor-associated antigen, a transmembrane domain protein, an ion channelprotein, and/or a G-protein coupled receptor.

In further preferred embodiments, the tumor associated antigen isselected from MAGE-A1, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A5, MAGE-A6,MAGE-A7, MAGE-A8, MAGE-A9, MAGE-A10, MAGE-A11, MAGE-A12, GAGE-I, GAGE-2,GAGE-3, GAGE-4, GAGE-5, GAGE-6, GAGE-7, GAGE-8, BAGE-I, RAGE-1,LB33/MUM-1, PRAME, NAG, MAGE-Xp2 (MAGE-B2), MAGE-Xp3 (MAGE-B3), MAGE-Xp4(MAGE-B4), MAGE-C1/CT7, MAGE-C2, NY-ESO-I, LAGE-I, SSX-I,SSX-2(HOM-MEL-40), SSX-3, SSX-4, SSX-5, SCP-I and XAGE, melanocytedifferentiation antigens, p53, ras, CEA, MUC1, PMSA, PSA, tyrosinase,Melan-A, MART-1, gp100, gp75, alpha-actinin-4, Bcr-Abl fusion protein,Casp-8, beta-catenin, cdc27, cdk4, cdkn2a, coa-1, dek-can fusionprotein, EF2, ETV6-AML1 fusion protein, LDLR-fucosyltransferaseAS fusionprotein, HLA-A2, HLA-A11, hsp70-2, KIAAO205, Mart2, Mum-2, and 3,neo-PAP, myosin class I, OS-9, pml-RAR alpha fusion protein, PTPRK,K-ras, N-ras, Triosephosphate isomerase, GnTV, Herv-K-mel, NA-88, SP17,and TRP2-Int2, (MART-I), E2A-PRL, H4-RET, IGH-IGK, MYL-RAR, Epstein Barrvirus antigens, EBNA, human papillomavirus (HPV) antigens E6 and E7,TSP-180, MAGE-4, MAGE-5, MAGE-6, p185erbB2, p180erbB-3, c-met, nm-23H1,PSA, TAG-72-4, CA 19-9, CA 72-4, CAM 17.1, NuMa, K-ras,alpha-fetoprotein, 13HCG, BCA225, BTAA, CA 125, CA 15-3 (CA 27.29\BCAA),CA 195, CA 242, CA-50, CAM43, CD68\KP1, CO-029, FGF-5, G250, Ga733(EpCAM), HTgp-175, M344, MA-50, MG7-Ag, MOV18, NB\170K, NY-CO-1, RCAS1,SDCCAG16, TA-90 (Mac-2 binding protein\cyclophilin C-associatedprotein), TAAL6, TAG72, TLP, TPS, tyrosinase related proteins, TRP-1,TRP-2, and cytomegalovirus phosphoprotein 65 (pp65).

In another preferred embodiment, the peptidogenic protein is a proteinthat is part of a complex. For example, buried interfacial residues maybe targeted for amino acid substitution, in e.g., proteins such asgp120, which is an envelope glycoprotein that forms a trimeric complexand is involved in HIV infection.

In a preferred embodiment, the mixture of polynucleotides encoding thepeptidogenic proteins can be synthesized in vitro. The polynucleotidescan also preferably comprise either DNA or mRNA. In preferredembodiments, the polynucleotides are in vitro transcribed (IVT) mRNA.The mRNA, including the IVT mRNA, can further comprise a poly(A) tailand/or a 5′ cap. In another preferred embodiment, the mRNA can betranslated in vitro to produce the peptidogenic proteins, including byuse of coupled in vitro transcription/translation (IVTT).

The mixture of polynucleotides can comprise sequences encoding differentpeptidogenic proteins derived from either the same starting protein orfrom multiple starting proteins. In further preferred embodiments, thepolynucleotides can be associated with a targeting component thattargets the polynucleotides to a cell or organ. Alternatively, thepolynucleotides can be unassociated with a targeting component. Thepolynucleotides encoding the peptidogenic proteins may also comprise avector sequence.

Mixtures of these polynucleotides as well as animals (geneticallymodified or not genetically modified) expressing mixtures ofpolynucleotides are also contemplated. In preferred embodiments, theanimal is a mammal and in further preferred embodiments, the mammal is ahuman, a mouse, a rabbit, a llama, or a cow.

In further preferred embodiments, the method induces an immune response.The immune response can occur in vivo, ex vivo and/or in vitro.

The polynucleotides encoding the peptidogenic proteins, including, butnot limited to mixtures of polynucleotides, can be delivered to theanimal by injection. In preferred embodiments, the injection occurs inthe muscle of the animal. The delivery of the polynucleotides to theanimal can be used for vaccination purposes, in research, or antibodydevelopment.

In further preferred embodiments, the antibody produced by the describedmethods is recovered and isolated. In preferred embodiments, theantibody is a fully human antibody, a chimeric antibody, a single-chainantibody, a camelid antibody, a humanized antibody, a polyclonalantibody or a monoclonal antibody. In preferred embodiments, thepolyclonal antibody is further fractionated into single, isolatedantibody species. In other preferred embodiments, the produced antibodyis affinity matured, such as, for example, by phage display, yeastdisplay, ribosome display or by a panning technique.

Also contemplated are polynucleotides that encode the antibodiesproduced by the methods described herein. These antibody encodingpolynucleotides can also comprise a heterologous promoter and/or avector sequence.

The peptidogenic proteins and/or the mixtures of polynucleotidesencoding the peptidogenic proteins can also be used to vaccinate amammal. In preferred embodiments, the vaccine is a cancer vaccine, anHIV vaccine, an HCV vaccine, an HBV vaccine, an influenza virus vaccine,a MERS-CoV vaccine, a Zika vaccine, a malaria vaccine, and/or an ebolavirus vaccine comprising the peptidogenic proteins.

In further preferred embodiments, the invention is a method ofprocessing a peptidogenic protein wherein the method comprisesintroducing to an antigen presenting cell a peptidogenic protein,wherein the peptidogenic protein has altered conformational dynamics ascompared to a starting protein and wherein the peptidogenic protein hasa similar conformation to the starting protein; and permitting theantigen presenting cell to process and display T cell epitopes derivedfrom the peptidogenic protein.

In preferred embodiments, the antigen presenting cell is a dendriticcell, a B cell, a monocyte or a macrophage. In further preferredembodiments, the method is carried out in vitro or ex vivo. In furtherpreferred embodiments, the antigen presenting cell is transfected with apolynucleotide encoding the peptidogenic protein(s) and/or placed incontact with the peptidogenic protein(s). In further preferredembodiments the antigen presenting cell undergoes phagocytosis orpinocytosis of the peptidogenic protein(s) or polynucleotide(s).

DETAILED DESCRIPTION OF THE INVENTION

Overview

We describe herein a novel method of generating an immune response,including enhancing the generation of antibodies by using a protein's“peptidogenic potential” via altering the conformational dynamics of astarting protein while maintaining that protein's 3-D conformation.These peptidogenic proteins can then be used to mount an immuneresponse, used as a vaccine and/or to generate antibodies.

Thus, the invention is directed to a method of triggering an immuneresponse wherein said method comprises designing a mixture ofpeptidogenic proteins derived from a starting protein, wherein thepeptidogenic proteins have altered conformational dynamics as comparedto the starting protein and wherein the peptidogenic proteins aresimilar in conformation to the starting protein, introducing thepeptidogenic proteins to an animal and generating an immune response.The peptidogenic proteins can be introduced into the animals directly(by, for instance, inoculation or immunization) or can be expressed invivo by polynucleotides that have been introduced into the animal andwhich encode the peptidogenic proteins. Upon expression of thesepeptidogenic proteins, the immune response is triggered to generateantibodies preferably to both the peptidogenic proteins and to theoriginal starting protein.

Introduction of the polynucleotides can occur, for example, by eitherdirectly or after first performing ex vivo transfection of dendriticcells. Additionally, polynucleotides encoding the peptidogenic proteinscan be generated and introduced into an animal. The peptidogenicproteins can then be produced in the animal to generate antibodies tothe peptidogenic proteins. The methods described herein have thepotential to profoundly impact the immunogenicity of proteins. Preferredbiophysical and biochemical properties that are altered in the protein,include, but are not limited to conformational dynamics of a protein,the thermodynamic stability, MHC-II binding, and/or the proteasesusceptibility of the starting protein. The methods described herein canalso be used to simultaneously produce cross-reacting antibodies todifferent peptidogenic proteins (either derived from the same ordifferent starting proteins) which has the potential to profoundlychange the way in which antibodies are currently being generated as therepertoire of antibodies that can be obtained by a single injection inan animal has the potential to streamline antibody development andvaccination efficacy.

We have recognized that the conformational dynamics of a protein arecritical for the ability of the protein to mount an immune response. Thepropensity of an antigen to efficiently yield peptide fragments in vivoafter immunization we have termed “peptidogenicity.” Having the abilityto alter the conformational dynamics of a starting protein to design amixture of peptidogenic proteins which can be administered directly as aprotein mixture or simultaneously expressed in an animal by a mixture ofpolynucleotides has the potential to generate a broad repertoire ofantibodies with a single injection in a cost effective manner.

Thus, as disclosed herein, immunizing an animal with a mixture ofpeptidogenic proteins can robustly stimulate the immune system,generating stronger and/or better immune responses when placed incontact with an antigen presenting cell.

The immunization with a mixture (or combinatorial cocktail) ofpeptidogenic proteins is advantageous due to the complexity of theproteolytic attack on the protein antigen(s) that produces the peptides.For example, providing multiple different peptidogenic proteins havingdifferent amino acid sequences creates an environment where the “tuningmutation(s)” optimal for the production of a given peptide (T cellepitope) in the right time frame may be different from the mutationsoptimal for production of another peptide. For example, some cells, suchas dendritic cells, mediate T-cell responses during an activation phase.If these cells are presented with antigens outside of this activationwindow (e.g., before or after activation) then a T-cell response may notbe triggered. Thus, T-cells need to be presented with antigens at theappropriate time, which is governed by rates of protein degradation(e.g., proteolysis) in the antigen presenting cell, to trigger an immuneresponse. By giving the antigens as mixtures, a multiplicity ofdifferent peptidogenic proteins can be endocytosed by a single cell,which theoretically maximizes the diversity of the peptides produced anddisplayed by that cell. Alternatively, by giving the antigens asmixtures, a multiplicity of different peptidogenic proteins can beendocytosed by multiple cells, which theoretically maximizes thediversity of the peptides produced and displayed by these cells.Additionally, the peptidogenic proteins having increased conformationaldynamics may lead to an improved MHC class II binding which is expectedto maximize the immune response. For example, for proteins that arerelatively non-immunogenic and/or are not good vaccine componentsbecause of being too stable, and thus protease degradation is inhibitedand subsequent peptide presentation is thereby impoverished resulting inattenuation of the immune response in adaptive immunity, such proteinscould be altered as described herein to generate a mixture ofpeptidogenic proteins with altered conformational dynamics whilemaintaining a similar conformation as compared to the starting protein.

In preferred embodiments, a starting protein, also referred to as a teststarting protein, can be systematically mutated to alter thethermodynamic stability of the starting protein, without significantlyaltering the three-dimensional structure of the corresponding foldedprotein, to generate peptidogenic proteins having increasedpeptidogenicity while displaying essentially the same 3D(conformational) surface epitopes as the starting protein.

Thus, increasing the immunogenicity of a starting protein by alteringits conformational dynamics to produce numerous peptidogenic proteinswhich can then be simultaneously introduced into an animal will generatea robust immune response and has the potential to raise a broaderrepertoire of polyclonal antibodies which can be further fractionated(for example, by molecularly cloning via their respective encodingmRNAs) into single isolated species.

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by those of ordinary skillin the art, such as in the arts of peptide chemistry, cell culture andphage display, nucleic acid chemistry and biochemistry. Standardtechniques are used for molecular biology, genetic and biochemicalmethods (see Sambrook et al., Molecular Cloning: A Laboratory Manual,3rd ed., 2001, Cold Spring Harbor Laboratory Press, Cold Spring Harbor,N.Y.; Ausubel et al., Short Protocols in Molecular Biology (1999) 4^(th)ed., John Wiley & Sons, Inc.), which are incorporated herein byreference.

As used herein, “peptidogenicity” refers to the propensity of a proteinto efficiently yield a robust set of diverse peptides which can be usedto yield an immune response. Various assays exist for measuringpeptidogenicity (see, for example, So et al., FIGS. 2c-d; Thai et al.,FIG. 7c-f; and Delamarre et al., FIGS. 1b-c, 4b-c and 5a-b).

As used herein, a “peptidogenic protein” refers to a mutated proteinthat has been modified in its amino acid sequence to alter itsconformational dynamics as compared to the starting protein sequencewhile maintaining a similar conformation to the starting protein.

As used herein, “non-surface residues” are residues that are not surfaceaccessible with regard to the 3D structure of a protein, e.g., residuesthat are buried within the interior of the 3D structure of the nativeprotein. In preferred embodiments, “non-surface” residues are defined bythe method of Lee and Richards (see, e.g., Lee B et al., J. Mol. Biol.(1971); 55(3):379-IN4.doi:http://dx.doi.org/10.1016/0022-2836(71)90324-X.), where the relativesolvent accessibility of the residue in the native protein is less than50%, less than 40%, less than 30%, less than 25%, less than 20%, lessthan 10%, less than 5%, or 0%, or by the same method where thedifference between the absolute solvent accessible surface area and thesurface area in the fully extended Ala-X-Ala tripeptide (see, e.g.,Gready J E et al., Protein Science. (1997); 6(5):983-98. doi:10.1002/pro.5560060504.) is greater than 40 Å², greater than 50 Å²,greater than 60 Å², greater than 70 Å², greater than 80 Å², greater than90 Å², greater than 100 Å², greater than 110 Å², or greater than 120 Å².In further preferred embodiments, “non-surface” residues are defined asresidues with a solvent accessible surface area of less than 10 Å², lessthan 5 Å², less than 2.5 Å², or less than 1 Å², as calculated by astructural analysis software package familiar to those skilled in theart (e.g. UCSF Chimera (see, e.g., Pettersen E F et al., J. Comput.Chem. (2004); 25(13):1605-12. Epub 2004 Jul. 21.), PyMol (see, e.g.,Schrodinger, LLC. The PyMOL Molecular Graphics System, Version 1.8.2015.), etc.

As used herein, a “starting protein” or “test starting protein” refersto the amino acid sequence of the “original” or “reference” protein thatis used to derive the peptidogenic protein. In some examples, the“starting protein” can be a peptidogenic protein that has been furthermodified.

As used herein, an “immune response” refers to the humoral immuneresponse and/or the cell-mediated immune response that is triggered byan antigen presenting cell after processing a protein. In the humoralimmune response, B lymphocytes produce antibodies that react withnative, unprocessed antigens. These antigen-antibody reactions may insome cases involve cell-surface antigens that activate the complementcascade, which causes the lysis of cells bearing those antigens. In thecell-mediated immune response, T lymphocytes mobilize macrophages in thepresence of processed peptide antigens recognized as foreign. ActivatedT lymphocytes can also attack cells bearing foreign antigens directly.

As used herein, an “antigen presenting cell” refers to a cell that canbreak down (“process”) a protein into peptides and present the peptides,in conjunction with the MHC allele, preferably major HLA complex class Ior class II molecules, on the cell surface. Examples of antigenpresenting cells include, but are not limited to dendritic cells,macrophages, B cells, and monocytes.

As used herein, “conformational dynamics” is defined as the phenomenarelated conformational changes and flexibility of a protein structure inthe spatial arrangement of atoms or groups of atoms with respect to eachother in a protein molecule. Conformational dynamics include “breathing”motions and involve the vibration, bending, twisting, rotation, andother allowed modes of movement of the atoms joined by the covalentbonds in the protein molecule, governed by intrinsic restoring forcesbut modulated by non-covalent interactions such as hydrogen bonds, vander Waals forces, and electrostatic interactions. These motions cansubtly change the geometry of the protein on a sub-picosecond timescaleand can result in a vast diversity of conformational states on atime-scale of microseconds to milliseconds. Conformational moleculardynamics of proteins is often studied using computer simulations. See,for example, Shaw et al (2010) Science 330, 341. Also as used herein,the conformational dynamics of a starting protein can be altered bychemical modifications, amino acid substitutions, and other mutationssuch as deletions, insertion, truncations, or any combination thereof,etc. By stating that the conformational dynamics of the peptidogenicprotein is varied with regard to the wild type protein, it is meant thatthe one or more amino acid substitutions of the peptidogenic proteinresults in altered conformational dynamics as compared to the wild typeprotein.

As used herein, “thermodynamic stability” is defined in terms of achemical system where no or minimal energy is either released orconsumed, and thus no or minimal changes in thermal energy are presentand the system is in its lowest energy state under a given set ofexperimental conditions. Also as used herein, a “decrease inthermodynamic stability” or “decreased thermodynamic stability” meansthat the parameters pertaining to thermodynamic stability of thepeptidogenic protein are attenuated as compared to those of the startingprotein measured under the same conditions, and this decrease can beachieved in the peptidogenic protein by, but not limited to, alterationsto the molecular structure of the starting protein via chemicalmodifications, amino acid substitutions, and other genetic mutations.Methods of measuring a decrease in thermodynamic stability are known inthe art and described herein, and include protocols incorporating themeasurement of parameters such as melting temperature and urea- orguanidinium hydrochloride-induced equilibrium unfolding (denaturation).These parameters are typically arrived at by monitoring the proteinunfolding reaction as a function temperature or denaturant concentrationunder conditions of equilibrium or quasi-equilibrium. Methods formonitoring the unfolding reaction by measuring the concentration of theunfolded state relative to that of the folded state include, but are notlimited to, UV absorption, fluorescence, and circular dichroism. Thisapproach allows the calculation of a stabilization free energy (Gibbsfree energy) of the mutant protein relative to the stabilization freeenergy of the starting protein measured under the same conditions. Thedifference in free energy is typically denoted byΔΔG=ΔG_(mutant)−ΔG_(standard(e.g., wt)), where ΔG_(mutant) andΔG_(standard(e.g., wt)) are the stabilization free energies of themutant and “standard” (e.g., wt or wild type) proteins, respectively,and MG is the difference. ΔΔG>0 indicates a mutant protein that is lessstable than the standard protein, and ΔΔG<0 indicates a mutant proteinthat is more stable than the standard protein.

As used herein, a peptidogenic protein has a “similar conformation” to astarting protein if the 3-D structure is sufficiently maintained aftermutating non-surface residues of the protein (and, consequently,potentially modifying its overall conformational dynamics) to allow foran antibody to cross react with both the peptidogenic protein and thestarting protein. “Cross-reactivity” can be measured by a binding assayas described herein or as is well known in the art and is measured as a“binding affinity” which is based on dissociation constants (K_(D)), offrates (k_(off)), and/or on rates (k_(on)). The peptidogenic protein doesnot need to have an identical 3-D structure as the starting protein;just a sufficiently similar structure displaying similar 3Dconformational epitopes (including discontinuous epitopes), that willallow for an antibody to recognize both proteins, even though thebinding affinities may be nonidentical.

In the present invention, the term “antibody,” refers to immunoglobulinmolecules and immunologically active portions of immunoglobulinmolecules, i.e., molecules that contain an antigen binding site thatimmunospecifically binds the peptidogenic protein and/or the startingprotein. As such, the term antibody encompasses not only whole antibodymolecules, but also antibody fragments as well as variants (includingderivatives such as fusion proteins) of antibodies and antibodyfragments. Examples of molecules which are described by the term“antibody” in this application include, but are not limited to: singlechain Fvs (scFvs), Fab fragments, Fab′ fragments, F(ab′)₂, disulfidelinked Fvs (sdFvs), Fvs, and fragments comprising or alternativelyconsisting of, either a VL or a VH domain. The term “single chain Fv” or“scFv” as used herein refers to a polypeptide comprising a VL domain ofan antibody linked to a VH domain of an antibody. See Carter (2006)Nature Rev. Immunol. 6:243.

Additionally, antibodies of the invention include, but are not limitedto, monoclonal, multi-specific, bi-specific, human, humanized, mouse, orchimeric antibodies, single chain antibodies, camelid antibodies, Fabfragments, F(ab′) fragments, anti-idiotypic (anti-Id) antibodies(including, e.g., anti-Id antibodies to antibodies of the invention),domain antibodies and epitope-binding fragments of any of the above. Theimmunoglobulin molecules of the invention can be of any type (e.g., IgG,IgE, IgM, IgD, IgA and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1and IgA2) or subclass of immunoglobulin molecule.

Most preferably, the antibodies are human antibodies. As used herein,“human” antibodies include antibodies having the amino acid sequence ofa human immunoglobulin and include antibodies isolated from humanimmunoglobulin libraries and xenomice or other organisms that have beengenetically engineered to produce human antibodies. For a detaileddiscussion of a few of the technologies for producing human antibodiesand human monoclonal antibodies and protocols for producing suchantibodies, see, e.g., PCT publications WO 98/24893; WO 92/01047; WO96/34096; WO 96/33735; European Patent No. 0 598 877; U.S. Pat. Nos.5,413,923; 5,625,126; 5,633,425; 5,569,825; 5,661,016; 5,545,806;5,814,318; 5,885,793; 5,916,771; and 5,939,598; and Lonberg and Huszar,Int. Rev. Immunol. 13:65-93 (1995).

Human antibodies or “humanized” chimeric monoclonal antibodies can beproduced using techniques described herein or otherwise known in theart. For example, methods for producing chimeric antibodies are known inthe art. See, for review the following references: Morrison, Science229:1202 (1985); Oi et al., BioTechniques 4:214 (1986); Cabilly et al.,U.S. Pat. No. 4,816,567; Taniguchi et al., EP 171496; Morrison et al.,EP 173494; Neuberger et al., WO 8601533; Robinson et al., WO 8702671;Boulianne et al., Nature 312:643 (1984); Neuberger et al., Nature314:268 (1985).

The antibodies of the present invention may be monovalent, bivalent,trivalent or multivalent. For example, monovalent scFvs can bemultimerized either chemically or by association with another protein orsubstance. A scFv that is fused to a hexahistidine tag or a Flag tag canbe multimerized using Ni-NTA agarose (Qiagen) or using anti-Flagantibodies (Stratagene, Inc.).

The antibodies of the present invention may be monospecific, bispecific,trispecific or of greater multispecificity. Multispecific antibodies maybe specific for the peptidogenic protein, for more than one peptidogenicprotein, for the starting protein, or they may be specific for both thepeptidogenic protein and/or the starting protein and a heterologousepitope, such as a heterologous polypeptide or solid support material.See, e.g., PCT publications WO 93/17715; WO 92/08802; WO 91/00360; WO92/05793; Tutt, et al., J. Immunol. 147:60-69 (1991); U.S. Pat. Nos.4,474,893; 4,714,681; 4,925,648; 5,573,920; 5,601,819; Kostelny et. al.,J. Immunol. 148:1547-1553 (1992).

The term “fragment” as used herein refers to a polypeptide comprising anamino acid sequence of at least 5 amino acid residues, at least 10 aminoacid residues, at least 15 amino acid residues, at least 20 amino acidresidues, at least 25 amino acid residues, at least 30 amino acidresidues, at least 35 amino acid residues, at least 40 amino acidresidues, at least 45 amino acid residues, at least 50 amino acidresidues, at least 60 amino residues, at least 70 amino acid residues,at least 80 amino acid residues, at least 90 amino acid residues, atleast 100 amino acid residues, at least 125 amino acid residues, atleast 150 amino acid residues, at least 175 amino acid residues, atleast 200 amino acid residues, or at least 250 amino acid residues, ofthe amino acid sequence of the peptidogenic protein or starting protein.In some embodiments, a fragment may also refer to a polypeptidecomprising an amino acid sequence of about 8 to 24 amino acid residues,or about 5 to 30 amino acid residues.

The term “fusion protein” as used herein refers to a polypeptide thatcomprises, or alternatively consists of, an amino acid sequence of thepeptidogenic protein, the starting protein, and/or the antibody raisedagainst the peptidogenic protein and an amino acid sequence of one ormore heterologous peptides and/or polypeptides. For vaccineapplications, the heterologous polypeptide sequence fused to thepeptidogenic protein is preferably from a viral protein.

The term “host cell” as used herein refers to the particular subjectcell transfected with a nucleic acid molecule and the progeny orpotential progeny of such a cell. Progeny may not be identical to theparent cell transfected with the nucleic acid molecule due to mutationsor environmental influences or developmental steps that may occur insucceeding generations or integration of the nucleic acid molecule intothe host cell genome.

A “conservative amino acid substitution” is one in which the amino acidresidue is replaced with an amino acid residue having a side chain witha similar chemical nature (e.g., size, charge, steric features [e.g.,beta-branched vs. non-beta-branched], polarity [hydrophilic vs.hydrophobic], aromatic vs. non-aromatic, etc.). Whether or not aparticular substitution is deemed “conservative” may also depend on thestructural context in the folded protein in which a substitution occurs.Amino acid side chains may be chemically similar in one respect butchemically dissimilar in another, and the context may determine which ofthese properties dominates in terms of how “conservative” (i.e., leastdisruptive) that particular substitution is. Families of amino acidresidues having chemically similar side chains have been defined in theart. These families include amino acids with basic side chains (e.g.,lysine, arginine), acidic side chains (e.g., aspartic acid, glutamicacid), uncharged polar side chains (e.g., asparagine, glutamine, serine,threonine), nonpolar side chains (e.g., glycine, alanine, valine,leucine, isoleucine, proline, phenylalanine, methionine, tryptophan),beta-branched side chains (e.g., threonine, valine, isoleucine) andaromatic side chains (e.g., tyrosine, phenylalanine, tryptophan,histidine). Some side chains have a hybrid character that ispH-dependent in physiologically relevant pH ranges. For example,histidine (pKa˜6) becomes more positively-charged (basic) below pH 6,and polar but substantially uncharged at pH 7.5 and above. Cysteine(pKa˜8.5) is substantially uncharged (and not particularly polar) belowpH 8, but negatively charged (and acidic) at pH 9. The tyrosine phenolicside chain is also partially ionized and negatively charged at higherpH. Moreover, the local electrostatic environment (context) of the restof the protein can shift these effective pH values substantially.Moreover, an acidic protein cysteine thiolate side chain can react, viathiol-disulfide exchange involving an intermediary disulfide-containingcompound such as oxidized glutathione, with another protein cysteinethiol to form an intramolecular disulfide bond; such bonds are highlyhydrophobic (non-polar). Additionally, both naturally occurring and/ornon-naturally occurring amino acids can be used in the peptidogenicproteins.

Mutations can be introduced in a site-directed fashion or randomly alongall or part of the coding sequence. Libraries of mutants can be designedto introduce a single amino acid substitution, two amino acidsubstitutions, three amino acid substitutions, four amino acidsubstitutions, and so forth, up to nineteen amino acid substitutions ata given residue site. In still other embodiments, libraries of mutantscan be designed to introduce more than nineteen amino acid substitutions(including natural and non-natural amino acids) at a given residue site.In addition, libraries can be combinatorially designed to simultaneouslyproduce multiple mutations at two sites, three sites, four sites, and soon. Following mutagenesis, the encoded protein may routinely beexpressed and the conformational dynamics of the encoded protein and/orpeptidogenicity can be determined using techniques described herein orby routinely modifying techniques known in the art. The resultant mutantproteins can be screened and evaluated for altered thermodynamicstability or for peptidogenicity or for similar conformation to thestarting protein. Alternatively, the expressed protein “output” from thedesigned library can be used to immunize an animal without priorscreening for protein properties.

As used herein, the “patient” or “subject suitable for treatment” may bea mammal, such as a rodent (e.g. a guinea pig, a hamster, a rat, amouse), murine (e.g. a mouse), canine (e.g. a dog), feline (e.g. a cat),equine (e.g. a horse), a primate, simian (e.g. a monkey or ape), amonkey (e.g. marmoset, baboon, rhesus macaque), an ape (e.g. gorilla,chimpanzee, orangutan, gibbon), or a human. In other embodiments,non-human mammals, especially mammals that are conventionally used asmodels for demonstrating therapeutic efficacy in humans (e.g. murine,primate, porcine, canine, camels, llamas, or rabbits) may be employed.

Other aspects and embodiments of the invention provide the aspects andembodiments described herein with the term “comprising” replaced by theterm “consisting of” and the aspects and embodiments described abovewith the term “comprising” replaced by the term “consisting essentiallyof”.

As used herein, “and/or” is to be taken as specific disclosure of eachof the two or more specified features or components with or without theothers. For example “A, B and/or C” is to be taken as specificdisclosure of each (i) A, (ii) B, (iii) C, (iv) A and B, (v) A and C,(vi) B and C and (vii) A and B and C, just as if each is set outindividually.

Methods of Altering the Conformational Dynamics of a Protein

A peptidogenic protein can be generated using standard molecular biologymutagenesis techniques well known in the art. For example, thepeptidogenic protein can be generated by random mutagenesis as is wellknown in the art, such as, for example, by error-prone PCR, randomnucleotide insertion or deletion or other methods prior torecombination.

To generate the peptidogenic protein, protein engineering may beemployed. Recombinant DNA technology known to those skilled in the artcan be used to create peptidogenic proteins including single or multipleamino acid substitutions, deletions, insertions, or fusion proteins.Such peptidogenic proteins may be screened for those that have alteredconformational dynamics while maintaining a similar conformation to thestarting protein as described herein.

For example, to increase the conformational dynamics of the peptidogenicprotein, the following table, Table 1, shows the average change in Gibbsfree energy for exemplary amino acid substitutions in a range ofproteins, derived from Tables 1 and 2 of Loladze et al., J. Mol. Biol.320, 343-357 (2002) [note: this paper uses a non-standard conventionwhen expressing Gibbs free energies between mutant and wild typeproteins, namely using negative values to indicate destabilization(ΔΔG=ΔG(mutant)−ΔG(WT)); the standard convention is that positivechanges indicate destabilization (ΔΔG=ΔG(WT)−ΔG(mutant), see paragraph0040 above)]. For example, Val and Leu (and the other larger non-polaramino acid residues) can be substituted with smaller ones such as Ala,Thr, Asn, and/or Gly. In addition, the buried site of Glu in the nativeprotein structure, can be substituted with Leu, Val, Asn, Thr, Ser, Ala,and/or Gly. The types of single site amino acid substitutions showngenerally have little impact on the overall conformation of the startingprotein.

TABLE 1 Amino Acid Substitution Average Gibbs Free Energy difference(multiple positions in between mutant and wild type at core variousproteins) residues within a protein ΔΔG (kJ/mol) Val −> Ala −12.1(±3.3)Val −> Thr −11.3(±3.7) Val −> Asn −21.5(±1.0) Leu −> Ala −14.2(±4.2)

Another illustrative paper describing destabilizing mutations in thecore of a protein that increase conformational dynamics is Kim et al(1993) Protein Sci. 2:588-596. In this work, the authors show that themutations Phe22→Ala (2.1 kcal/mol), Tyr23→Ala (7.0 kcal/mol), Tyr35→Gly(5.7 kcal/mol), Asn43→Gly (6.0 kcal/mol), and Phe45→Ala (7.2 kcal/mol)destabilize bovine pancreatic trypsin inhibitor (BPTI) at pH 3.5 by therespective amounts shown in parentheses, without seriously disruptingthe overall 3D structure of BPTI.

In addition, genetic deletions, insertions, inversions, repeats, andtype substitutions selected according to general rules known in the artshould have little effect on activity. For example, guidance concerninghow to make phenotypically silent amino acid substitutions is providedin Bowie, J. U. et at., “Deciphering the Message in Protein Sequences:Tolerance to Amino Acid Substitutions,” Science 247:1306-1310 (1990),wherein the authors indicate that there are two main approaches forstudying the tolerance of an amino acid sequence to change. The firstmethod relies on the process of evolution, in which mutations are eitheraccepted or rejected by natural selection. The second approach usesgenetic engineering to introduce amino acid changes at specificpositions of a cloned gene and selections or screens to identifysequences that maintain functionality.

As the authors state, these studies have revealed that proteins aresurprisingly tolerant of amino acid substitutions. The authors furtherindicate which amino acid changes are likely to be permissive at acertain position of the protein. For example, most buried amino acidresidues require nonpolar side chains, whereas few features of surfaceside chains are generally conserved. Other such phenotypically silentsubstitutions are described in Bowie, J. U. et al., supra, and thereferences cited therein. Typically seen as conservative substitutionsare the replacements, one for another, among the aliphatic amino acidsAla, Val, Leu and Ile; interchange of the hydroxyl-bearing residues, Serand Thr; exchange of the acidic residues, Asp and Glu; substitutionbetween the sidechain amide-bearing residues, Asn and Gln; exchange ofthe basic amino acids, Lys and Arg; and replacements among the aromaticresidues, Phe and Tyr.

In preferred embodiments, the conformational dynamics of the startingprotein is altered by replacing: (a) at least one threonine with avaline, alanine, glycine or serine; or (b) at least one cysteine withalanine, valine, glycine, serine or threonine; or (c) at least onevaline with alanine, glycine, leucine or isoleucine; or (d) at least oneleucine with alanine, valine, glycine, or isoleucine; or (e) at leastone isoleucine with alanine, valine, isoleucine, or glycine; or (f) atleast one proline, methionine, phenylalanine, tyrosine, or tryptophanwith alanine, valine, leucine, isoleucine, or glycine; or (g) at leastone aspartic acid with glutamic acid, glutamine, asparagine, glycine,serine, threonine, alanine, valine, leucine, isoleucine; or (h) at leastone glutamic acid with aspartic acid, glutamine, asparagine, glycine,serine, threonine, alanine, valine, leucine, or isoleucine; or (i) atleast one lysine with arginine, histidine, glycine, serine, threonine,alanine, valine, leucine, or isoleucine; or (j) at least one argininewith lysine, histidine, glycine, serine, threonine, alanine, valine,leucine, or isoleucine; or (k) at least one histidine with lysine,arginine, glycine, serine, threonine, alanine, valine, leucine,isoleucine, or glutamine; or (l) at least one alanine with a glycine orproline; or (m) at least one asparagine with a glycine, alanine, serine,threonine, glutamine, aspartic acid, or glutamic acid; or (n) at leastone glutamine with a glycine, alanine, serine, threonine, asparagine,aspartic acid, glutamic acid, or histidine; or (o) at least one glycinewith an alanine or proline; or (p) at least one residue with anon-natural amino acid; or (q) any combination of (a)-(p). In stillfurther preferred embodiments, the conformational dynamics of thestarting protein is altered by replacing: (a) at least one tryptophanwith tyrosine, phenylalanine, methionine, histidine, isoleucine,leucine, valine, alanine or glycine; or (b) at least one tyrosine withphenylalanine, methionine, histidine, isoleucine, leucine, valine,alanine or glycine; or (c) at least one phenylalanine with tyrosine,methionine, histidine, isoleucine, leucine, valine, alanine or glycine;or (d) at least one proline with methionine, leucine, isoleucine,valine, alanine, or glycine; or (e) at least one histidine withphenylalanine, tyrosine, methionine, isoleucine, leucine, valine,alanine, glycine, lysine, arginine, serine, threonine, asparagine, orglutamine; or (f) at least one methionine with isoleucine, leucine,valine, alanine or glycine; or (g) at least one isoleucine with leucine,valine, alanine or glycine; or (h) at least one leucine with isoleucine,valine, alanine or glycine; or (i) at least one valine with alanine,glycine, leucine, or isoleucine; or (j) at least one cysteine withalanine, valine, glycine, serine or threonine; or (k) at least oneaspartic acid with glutamic acid, glutamine, asparagine, glycine,serine, threonine, alanine, valine, leucine, or isoleucine; or (l) atleast one glutamic acid with aspartic acid, glutamine, asparagine,glycine, serine, threonine, alanine, valine, leucine, or isoleucine; or(m) at least one alanine with a glycine or proline; or (n) at least oneserine with alanine or glycine; or (o) at least one glycine with alanineor proline; or (p) at least one lysine with arginine, histidine,glycine, serine, threonine, alanine, valine, methionine, leucine orisoleucine; or (q) at least one asparagine with glycine, alanine,serine, threonine, valine, leucine, isoleucine, glutamine, aspartic acidor glutamic acid; or (r) at least one glutamine with glycine, alanine,serine, threonine, valine, leucine, isoleucine, glutamine, asparticacid, glutamic acid, or histidine; or (s) at least one arginine withlysine, histidine, glycine, serine, threonine, alanine valine,methionine, leucine, or isoleucine; or (t) at least one threonine withvaline, alanine, glycine or serine; or (u) a hydrophobic residue with asmaller, similar hydrophobic residue; or (v) at least one residue with anon-natural amino acid; or (w) any of the above combinations. In someembodiments, hydrophobic resides are targeted for replacement.

Amino acids in the starting protein that are essential for function,conformation, and/or structure and positioned on the protein surface vs.internal can be identified by methods known in the art, such assite-directed mutagenesis or alanine-scanning mutagenesis (Cunninghamand Wells, Science 244: 1081-1085 (1989)). The latter procedureintroduces single alanine mutations at every residue in the molecule.The resulting mutant molecules are then tested for those having alteredconformational dynamics while maintaining a similar conformation to thestarting protein.

In an additional embodiment, the amino acid sequence of the startingprotein has one or more amino acids (for example, 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 15, 20, 30 or 50 amino acids) replaced with the substitutedamino acids as described above (either conservative or non-conservativesubstitutions) to produce the peptidogenic protein. For example,substitutions in positions not involving a starting protein's activityand/or internal to the protein structure can be readily made. Sites thatare critical for ligand-receptor binding can also be determined bystructural analysis such as crystallization, nuclear magnetic resonanceor photoaffinity labeling (Smith et al., J. Mol. Biol. 224:899-904(1992); and de Vos et al. Science 255:306-312 (1992)).

Recombinant DNA technology that employs combinatorial mutagenesis andsynthetic DNA synthesis approaches known to those skilled in the art canalso be used to create a peptidogenic protein including single ormultiple amino acid substitutions, deletions, additions or fusionproteins. Such modified polypeptides may be then screened for alteredconformational dynamics while maintaining a similar conformation as thestarting protein.

Thus, a peptidogenic protein can be made where one or more amino acidresidues are deleted, added, or substituted to generate peptidogenicproteins having altered conformation dynamics. For example, residues inthe hydrophobic “core” of the protein can be substituted with non-polarresidues having smaller side chains (supra) in order to create cavitiesin the core and disrupt the packing, and cysteine residues can bedeleted or substituted with other amino acid residues in order toeliminate disulfide bridges (which are often found in protein cores). Insome embodiments, at least one disulfide bond is eliminated in thestarting protein, such as, for example, replacing the cysteines withalanines, serines, and/or glycines, etc. In further preferredembodiments, both cysteines involved in the formation of the at leastone disulfide bond are replaced with alanines, serines, and/or glycines,or preferably with alanines or glycines, etc.

The peptidogenic proteins are preferably provided in an isolated form,and preferably are substantially purified. Additionally, thepeptidogenic proteins would display a stable 3D conformational epitopefor B-cell activation while synthesized peptides (such as by chemicalsynthesis) can be co-administered, which could optimize the epitopes forMHC-II presentation. Alternatively, the peptidogenic proteins andpeptides can be expressed by a mixture of polynucleotides. In stillother embodiments, peptidogenic proteins can be combined with a wildtype starting protein and synthetic peptide(s) to elicit an immuneresponse.

In some embodiments, the rate of polypeptide degradation may be adjustedin order to produce an optimal mix of peptides, and in the right timeframe, to allow maximal diversity of the displayed peptides on theantigen presenting cells.

Immunization with mixtures (such as combinatorial cocktails) of antigensis advantageous due to the complexity of the proteolytic attack on theprotein antigen(s) that produce the peptides for display. Thus, the“tuning mutation(s)” optimal for the production of a given peptide (Tcell epitope) in the right time frame may be different from themutations optimal for production of another peptide. By giving theantigens as mixtures, a multiplicity of different mutant proteins may beendocytosed by a single cell or multiple cells, which maximizes thediversity of the peptides produced and displayed by that cell.

Combinatorial immunization, in which subjects are immunized with two ormore distinct antigens that have the same overall surface features (i.e.cross-reacting B-cell epitopes) but with different conformationaldynamics, enriches the diversity of T-cell epitopes. This combinatorialapproach, which includes hundreds or even thousands of differentimmunogens in a single inoculation (both protein-based andnucleotide-based) may vastly increase the B-cell epitope repertoire,since every molecule in the mix can contribute to one or more uniqueT-cell epitopes while maintaining a wild type-like conformation. In someaspects, because the wild-type configuration is maintained, the B-cellepitope repertoire is biased towards the most stable (and presumablywild type-like) molecules in the ensemble.

Peptidogenic Protein has a Similar Conformation as a Starting Protein

The operational test of whether the peptidogenic protein has a “similarconformation to the starting protein” is whether or not a cross-reactingantibody, especially an antibody that recognizes a conformational (3D)epitope, specifically binds to both the peptidogenic protein and thestarting protein. In the present invention “cross-reactivity” or a“cross-reacting antibody” is defined in terms of “binding affinity”which can be measured based on dissociation constant (K_(D)), off rate(k_(off)), and/or on rate (k_(on)).

For example, a cross-reacting antibody binds to both the peptidogenicprotein and the starting protein at a dissociation constant or K_(D)less than or equal to 5×10⁻⁶ M, 10⁻⁶ M, 5×10⁻⁷ M, 10⁻⁷ M, 5×10⁻⁸ M, or10⁻⁸ M. Even more preferably, a cross-reacting antibody binds to boththe peptidogenic protein and the starting protein at a dissociationconstant K_(D) less than or equal to 5×10⁻⁹M, 10⁻⁹M, 5×10⁻¹⁰M, 10⁻¹⁰ M,5×10⁻¹¹M, 10⁻¹¹ M, 5×10⁻¹²M, 10⁻¹²M, 5×10⁻¹³ M, 10⁻¹³ M, 5×10⁻¹⁴M, or10⁻¹⁴ M. The invention encompasses a dissociation constant or K_(D) forthe peptidogenic protein and/or the starting protein that is within anyone of the ranges that are between each of the individual recitedvalues. Additionally, it is specifically contemplated that the K_(D) forthe antibody that binds to a peptidogenic protein may not be identicalto its K_(D) with respect to the starting protein, and in preferredembodiments, the K_(D) for the antibody that hinds to the peptidogenicprotein is less than the K_(D) for its binding to the starting protein.It is understood that, operationally, K_(D) in this case refers to thefunctional affinity of the antibody for the antigen. Functional or“apparent” affinity may be enhanced in multivalent antibodies thatcontain multiple interacting sites (e.g., Fab arms) that can bind to theantigen (“avidity effect”).

Additionally, a cross-reacting antibody binds to both the peptidogenicprotein and the starting protein with an off rate (k_(off)) of less thanor equal to 5×10⁻² sec⁻¹, 10⁻² sec⁻¹, 5×10⁻³ sec⁻¹ or 10⁻³ sec⁻¹. Morepreferably, a cross-reacting antibody binds to both the peptidogenicprotein and the starting protein at off rate (k_(off)) of less than orequal to 5×10⁻⁴ sec⁻¹, 10⁻¹ sec⁻¹, 5×10⁻⁵ sec⁻¹, or 10⁻⁵ sec⁻¹, 5×10⁻¹sec⁻¹, 10⁻⁶ sec⁻¹, 5×10⁻⁷ sec⁻¹ or 10⁻⁷ sec⁻¹. The invention encompassesan off rate (k_(off)) for the peptidogenic protein and/or the startingprotein that is within any one of the ranges that are between each ofthe individual recited values. Additionally, it is specificallycontemplated that the k_(off) of the antibody for the peptiflogenicprotein may not be identical to the k_(off) of the starting protein, andin preferred embodiments, the (k_(off)) for the binding of the antibodyto the peptidogenic protein is greater than the (k_(off)) for thebinding of the antibody to the starting protein.

Assays to test for the cross-reactivity are described herein or areknown in the art. For example, binding assays may be performed insolution (e.g., Houghten, Bio/Techniques 13:412-421(1992)), on beads(e.g., Lam, Nature 354:82-84 (1991)), on chips (e.g., Fodor, Nature364:555-556 (1993)), on bacteria (e.g., U.S. Pat. No. 5,223,409), onspores (e.g., U.S. Pat. Nos. 5,571,698; 5,403,484; and 5,223,409), onplasmids (e.g., Cull et al., Proc. Natl. Acad. Sci. USA 89:1865-1869(1992)) or on phage (e.g., Scott and Smith, Science 249:386-390 (1990);Devlin, Science 249:404-406 (1990); Cwirla et al., Proc. Natl. Acad.Sci. USA 87:6378-6382 (1990); and Felici, J. Mol. Biol. 222:301-310(1991)). Examples of such assays are described further below in theExamples.

Use of the Peptidogenic Protein to Generate Antibodies

The peptidogenic protein can be used to generate antibodies by methodswell known by the skilled artisan, such as, for example, methodsdescribed in the art. See, for instance, Sutcliffe et al., supra; Wilsonet al., supra; Chow et al., Proc. Natl. Acad. Sci. USA 82:910-914(1985); and Bittle et al., J. Gen. Virol. 66:2347-2354 (1985). If invivo immunization is used, animals may be immunized with a peptidogenicprotein and/or a polynucleotide encoding the peptidogenic proteindescribed herein.

Animals such as rabbits, rats, mice, llamas, camels, and/or cows can beimmunized with the peptidogenic protein and/or a polynucleotide encodingthe peptidogenic protein. For instance, intraperitoneal and/orintradermal injection of emulsions containing about 100 micrograms of apeptidogenic protein or carrier protein and Freund's adjuvant or anyother adjuvant known for stimulating an immune response may be used.Several booster injections may be needed, for instance, at intervals ofabout two weeks, to provide a useful titer of anti-peptidogenic proteinantibody which can be detected, for example, by ELISA assay using freepeptidogenic protein adsorbed, directly or indirectly (e.g., via abiotinylated AviTag), to a solid surface. The titer of anti-peptidogenicprotein antibodies in serum from an immunized animal may be increased byselection of anti-peptidogenic protein antibodies, for instance, byadsorption to the peptidogenic protein on a solid support and elution ofthe selected antibodies according to methods well known in the art. Suchselections could also be done using the starting protein.

Additionally, antibodies generated by the disclosed methods can beaffinity matured using display technology, such as for example, phagedisplay, yeast display or ribosome display. In one example, single chainantibody molecules (“scFvs”) displayed on the surface of phage particlesare screened to identify those scFvs that immunospecifically bind to thepeptidogenic protein and/or the starting protein. The present inventionencompasses both scFvs and portions thereof that are identified toimmunospecifically bind to the peptidogenic protein and/or the startingprotein. Such scFvs can routinely be “converted” to immunoglobulinmolecules by inserting, for example, the nucleotide sequences encodingthe VH and/or VL domains of the scFv into an expression vectorcontaining the constant domain sequences and engineered to direct theexpression of the immunoglobulin molecule.

Recombinant expression of an antibody raised using the peptidogenicprotein and/or a polynucleotide encoding the peptidogenic protein of theinvention (including scFvs and other molecules comprising, oralternatively consisting of, antibody fragments or variants thereof(e.g., a heavy or light chain of an antibody of the invention or aportion thereof or a single chain antibody of the invention)), requiresconstruction of an expression vector(s) containing a polynucleotide thatencodes the antibody or fragment or variant thereof. Once apolynucleotide encoding an antibody molecule (e.g., a whole antibody, aheavy or light chain of an antibody, or variant or portion thereof(preferably, but not necessarily, containing the heavy or light chainvariable domain)), of the invention has been obtained, the vector(s) forthe production of the antibody molecule may be produced by recombinantDNA technology using techniques well known in the art. Thus, methods forpreparing an antibody by expressing a polynucleotide containing anantibody encoding nucleotide sequence are described herein. Methodswhich are well known to those skilled in the art can be used toconstruct expression vectors containing antibody coding sequences (aswell as the coding sequences for the peptidogenic protein) andappropriate transcriptional and translational control signals. Thesemethods include, for example, in vitro recombinant DNA techniques,synthetic techniques, and in vivo genetic recombination. The invention,thus, provides replicable vectors comprising a nucleotide sequenceencoding either the peptidogenic protein or an antibody raised to thepeptidogenic protein (e.g., a whole antibody, a heavy or light chain ofan antibody, a heavy or light chain variable domain of an antibody, or aportion thereof, or a heavy or light chain CDR, a single chain Fv, orfragments or variants thereof), operably linked to a promoter. Suchvectors may include the nucleotide sequence encoding the constant regionof the antibody molecule (see, e.g., PCT Publication WO 86/05807; PCTPublication WO 89/01036; and U.S. Pat. No. 5,122,464) and the variabledomain of the antibody may be cloned into such a vector for expressionof the entire heavy chain, the entire light chain, or both the entireheavy and light chains.

The expression vector(s) can be transferred to a host cell byconventional techniques and the transfected cells are then cultured byconventional techniques to produce either the peptidogenic protein orthe antibody that has been raised against a peptidogenic protein. Thus,the invention includes host cells containing polynucleotide(s) encodingthe peptidogenic protein or an antibody raised against the peptidogenicprotein (e.g., whole antibody, a heavy or light chain thereof, orportion thereof, or a single chain antibody of the invention, or afragment or variant thereof), operably linked to a heterologouspromoter. In preferred embodiments, for the expression of entireantibody molecules, vectors encoding both the heavy and light chains maybe co-expressed in the host cell for expression of the entireimmunoglobulin molecule, as detailed below.

A variety of host-expression vector systems may be utilized to expressthe peptidogenic protein or the antibody raised to the peptidogenicprotein. Such host-expression systems represent vehicles by which thecoding sequences of interest may be produced and subsequently purified,but also represent cells which may, when transformed or transfected,with the appropriate nucleotide coding sequences, express thepeptidogenic protein or the antibody raised to the peptidogenic protein.These include, but are not limited to, microorganisms such as bacteria(e.g., E. coli, B. subtilis) transformed with recombinant bacteriophageDNA, plasmid DNA or cosmid DNA expression vectors containing sequences;yeast (e.g., Saccharomyces, Pichia) transformed with recombinant yeastexpression vectors containing coding sequences; insect cell systemsinfected with recombinant virus expression vectors (e.g., baculovirus)containing coding sequences; plant cell systems infected withrecombinant virus expression vectors (e.g., cauliflower mosaic virus,CaMV; tobacco mosaic virus, TMV) or transformed with recombinant plasmidexpression vectors (e.g., Ti plasmid) containing coding sequences; ormammalian cell systems (e.g., COS, CHO, BHK, 293, 3T3 cells) harboringrecombinant expression constructs containing promoters derived from thegenome of mammalian cells (e.g., metallothionein promoter) or frommammalian viruses (e.g., the adenovirus late promoter; the vacciniavirus 7.5K promoter). Preferably, bacterial cells such as Escherichiacoli, and more preferably, eukaryotic cells, are used for the expressionof either the peptidogenic protein or a recombinant antibody molecule.For example, mammalian cells such as Chinese hamster ovary cells (CHO),in conjunction with a vector such as the major intermediate early genepromoter element from human cytomegalovirus is an effective expressionsystem (Foecking et al., Gene 45:101 (1986); Cockett et al.,Bio/Technology 8:2 (1990)).

In bacterial systems, a number of expression vectors may beadvantageously selected depending upon the intended use. For example,when a large quantity of a protein (whether a peptidogenic protein or anantibody raised against the peptidogenic protein) is to be produced,vectors which direct the expression of high levels of fusion proteinproducts that are readily purified may be desirable. Such vectorsinclude, but are not limited to, the E. coli expression vector pUR278(Ruther et al., EMBO 1. 2:1791 (1983)), in which the coding sequence maybe ligated individually into the vector in frame with the lac Z codingregion so that a fusion protein is produced; pIN vectors (Inouye &Inouye, Nucleic Acids Res. 13:3101-3109 (1985); Van Heeke & Schuster, J.Biol. Chem. 24:5503-5509 (1989)); and the like. pGEX vectors may also beused to express foreign polypeptides as fusion proteins with glutathione5-transferase (GST). In general, such fusion proteins are soluble andcan easily be purified from lysed cells by adsorption and binding tomatrix glutathione agarose beads followed by elution in the presence offree glutathione. The pGEX vectors are designed to include thrombin orFactor Xa protease cleavage sites so that the cloned target gene productcan be released from the GST moiety.

In an insect system, Autographa californica nuclear polyhedrosis virus(AcNPV) may be used as a vector to express a peptidogenic protein or anantibody raised against the peptidogenic protein. The virus grows inSpodoptera frugiperda cells. Coding sequences may be cloned individuallyinto non-essential regions (for example, the polyhedrin gene) of thevirus and placed under control of an AcNPV promoter (for example, thepolyhedrin promoter).

In mammalian host cells, a number of viral-based expression systems maybe utilized. In cases where an adenovirus is used as an expressionvector, the coding sequence of interest may be ligated to an adenovirustranscription/translation control complex, e.g., the late promoter andtripartite leader sequence. This chimeric gene may then be inserted inthe adenovirus genome by in vitro or in vivo recombination.

Insertion in a non-essential region of the viral genome (e.g., region E1or E3) will result in a recombinant virus that is viable and capable ofexpressing the peptidogenic protein or an antibody raised against thepeptidogenic protein in infected hosts (e.g., see Logan & Shenk, Proc.Natl. Acad. Sci. USA 8 1:355-359 (1984)).

Specific initiation signals may also be required for efficienttranslation of inserted coding sequences. These signals include the ATGinitiation codon and adjacent sequences. Furthermore, the initiationcodon must be in phase with the reading frame of the desired codingsequence to ensure translation of the entire insert. These exogenoustranslational control signals and initiation codons can be of a varietyof origins, both natural and synthetic. The efficiency of expression maybe enhanced by the inclusion of appropriate transcription enhancerelements, transcription terminators, etc. (see, e.g., Bittner et al.,Methods in Enzymol. 153:51-544 (1987)).

In addition, a host cell strain may be chosen which modulates theexpression of the inserted sequences, or modifies and processes the geneproduct in the specific fashion desired. Such modifications (e.g.,glycosylation) and processing (e.g., cleavage) of protein products maybe important for the function of the protein. Different host cells havecharacteristic and specific mechanisms for the post-translationalprocessing and modification of proteins and gene products. Appropriatecell lines or host systems can be chosen to ensure the correctmodification and processing of the foreign protein expressed, to thisend, eukaryotic host cells which possess the cellular machinery forproper processing of the primary transcript, glycosylation, andphosphorylation of the gene product may be used. Such mammalian hostcells include, but are not limited to, CHO, VERY, BHK, Hela, COS, NSO,MDCK, 293, 3T3, W138, and in particular, breast cancer cell lines suchas, for example, BT483, Hs578T, HTB2, BT2O and T47D, and normal mammarygland cell line such as, for example, CRL7O3O and HsS78Bst.

For long-term, high-yield production of recombinant proteins, stableexpression is preferred. For example, cell lines which stably expressthe peptidogenic protein or an antibody raised against the peptidogenicprotein may be engineered. Rather than using expression vectors whichcontain viral origins of replication, host cells can be transformed witha polynucleotide controlled by appropriate expression control elements(e.g., promoter, enhancer, sequences, transcription terminators,polyadenylation sites, etc.), and a selectable marker. Following theintroduction of the foreign polynucleotide, engineered cells may beallowed to grow for 1-2 days in an enriched media, and then are switchedto a selective media. The selectable marker in the recombinant plasmidconfers resistance to the selection and allows cells to stably integratethe plasmid into their chromosomes and grow to form foci which in turncan be cloned and expanded into cell lines. This method mayadvantageously be used to engineer cell lines which express thepeptidogenic protein or an antibody raised against the peptidogenicprotein.

A number of selection systems may be used, including but not limited to,the herpes simplex virus thymidine kinase (Wigler et al., Cell 11:223(1977)), hypoxanthineguanine phosphoribosyltransferase (Szybalska &Szybalski, Proc. Natl. Acad. Sci. USA 48:202 (1992)), and adeninephosphoribosyltransferase (Lowy et al., Cell 22:8 17 (1980)) genes canbe employed in tk-, hgprt- or aprt-cells, respectively. Also,antimetabolite resistance can be used as the basis of selection for thefollowing genes: dhfr, which confers resistance to methotrexate (Wigleret al., Natl. Acad. Sci. USA 77:357 (1980); O'Hare et al., Proc. Natl.Acad. Sci. USA 78:1527 (1981)); gpt, which confers resistance tomycophenolic acid (Mulligan & Berg, Proc. Natl. Acad. Sci. USA 78:2072(1981)); neo, which confers resistance to the aminoglycoside G-418(Goldspiel et al., Clinical Pharmacy, 12: 488-505 (1993); Wu and Wu,Biotherapy 3:87-95 (1991); Tolstoshev, Ann. Rev. Pharmacol. Toxicol.32:573-596 (1993); Mulligan, Science 260:926-932 (1993); and Morgan andAnderson, Ann. Rev. Biochem. 62: 191-217 (1993); TIB TECH 11(5):155-2 15(May; 1993)); and hygro, which confers resistance to hygromycin(Santerre et al., Gene 30:147 (1984)). Methods commonly known in the artof recombinant DNA technology may be routinely applied to select thedesired recombinant clone, and such methods are described, for example;in Ausubel et al. (eds.), Current Protocols in Molecular Biology, JohnWiley & Sons, N.Y. (1993); Kriegler, Gene Transfer and Expression, ALaboratory Manual, Stockton Press, N Y (1990); and in Chapters 12 and13, Dracopoli et al. (eds), Current Protocols in Human Genetics, JohnWiley & Sons, N.Y. (1994); Colberre-Garapin et al., J. Mol. Biol. 150:1(1981).

The expression levels of a peptidogenic protein or an antibody raisedagainst the peptidogenic protein can be increased by vectoramplification (for a review, see Bebbington and Hentschel, The use ofvectors based on gene amplification for the expression of cloned genesin mammalian cells in DNA cloning, Vol. 3. (Academic Press, New York,1987)). When a marker in the vector system expressing a peptidogenicprotein or an antibody raised against the peptidogenic protein isamplifiable, an increase in the level of inhibitor present in the hostcell culture will increase the number of copies of the marker gene.Since the amplified region is associated with the coding sequence,production of the peptidogenic protein or an antibody raised against thepeptidogenic protein will also increase (Crouse et al., Mol. Cell. Biol.3:257 (1983)).

Other elements that can be included in vector sequences includeheterologous signal peptides (secretion signals), membrane anchoringsequences, introns, alternative splice sites, translation start and stopsignals, inteins, biotinylation sites and other sites promotingpost-translational modifications, purification tags, sequences encodingfusions to other proteins or peptides, separate coding regions separatedby internal ribosome reentry sites, sequences encoding “marker” proteinsthat, for example, confer selectability (e.g., antibiotic resistance) orsortability (e.g., fluorescence), modified nucleotides, and other knownpolynucleotide cis-acting features not limited to these examples.

In the case of antibodies, the host cell may be co-transfected with twoexpression vectors of the invention, the first vector encoding a heavychain derived polypeptide and the second vector encoding a light chainderived polypeptide. The two vectors may contain identical selectablemarkers which enable equal expression of heavy and light chainpolypeptides. Alternatively, a single vector may be used which encodes,and is capable of expressing, both heavy and light chain polypeptides.In such situations, the light chain is preferably placed before theheavy chain to avoid an excess of toxic free heavy chain (Proudfoot,Nature 322:52 (1986); Kohler, Proc. Natl. Acad. Sci. USA 77:2 197(1980)). The coding sequences for the heavy and light chains maycomprise cDNA or genomic DNA or synthetic DNA sequences.

Once a peptidogenic protein or an antibody raised against thepeptidogenic protein has been produced by recombinant expression, it maybe purified by any method known in the art for purification of aprotein, for example, by chromatography (e.g., ion exchange, affinity(particularly by Protein A affinity and immunoaffinity for the specificantigen), and sizing column chromatography), centrifugation,differential solubility, or by any other standard technique for thepurification of proteins. Further, a peptidogenic protein or an antibodyraised against the peptidogenic protein may be fused to heterologouspolypeptide sequences described herein or otherwise known in the art tofacilitate purification.

In one example, the peptidogenic protein or the antibody raised to thepeptidogenic protein described herein may be fused with the constantdomain of immunoglobulins (IgA, IgE, IgG, IgM), or portions thereof(CH1, CH2, CH3, or any combination thereof and portions thereof), oralbumin (including but not limited to recombinant human albumin orfragments or variants thereof (see, e.g., U.S. Pat. No. 5,876,969,issued Mar. 2, 1999, EP Patent 0 413 622, and U.S. Pat. No. 5,766,883,issued Jun. 16, 1998), resulting in chimeric polypeptides. Such fusionproteins may facilitate purification and may increase half-life in vivo.This has been shown for chimeric proteins consisting of the first twodomains of the human CD4-polypeptide and various domains of the constantregions of the heavy or light chains of mammalian immunoglobulins. See,e.g., EP 394,827; Traunecker et al., Nature, 331:84-86 (1988). Enhanceddelivery of an antigen across the epithelial barrier to the immunesystem has been demonstrated for antigens (e.g., insulin) conjugated toan FcRn binding partner such as IgG or Fe fragments (see, e.g., PCTPublications WO 96/22024 and WO 99/04813). IgG Fusion proteins that havea disulfide-linked dimeric structure due to the IgG portion disulfidebonds have also been found to be more efficient in binding andneutralizing other molecules than monomeric polypeptides or fragmentsthereof alone. See, e.g., Fountoulakis et al., J. Biochem.,270:3958-3964 (1995). Nucleic acids encoding the peptidogenic protein orantibodies described herein can also be recombined with a gene ofinterest as an epitope tag (e.g., the hemagglutinin (“HA”) tag or flagtag) to aid in detection and purification of the expressed polypeptide.For example, a system described by Janknecht et al. allows for the readypurification of non-denatured fusion proteins expressed in human celllines (Janknecht et al., 1991, Proc. Natl. Acad. Sci. USA 88:8972-897).In this system, the gene of interest is subcloned into a vacciniarecombination plasmid such that the open reading frame of the gene istranslationally fused to an amino-terminal tag consisting of sixhistidine residues. The tag serves as a matrix-binding domain for thefusion protein. Extracts from cells infected with the recombinantvaccinia virus are loaded onto Ni2+ nitriloacetic acid-agarose columnand histidine-tagged proteins can be selectively eluted withimidazole-containing buffers.

Vaccination

A mixture of peptidogenic proteins and/or polynucleotides encoding thepeptidogenic proteins can be used to vaccinate an animal. Thisvaccination may lead to the raising of antibodies to the peptidogenicproteins. A subject suitable for treatment as described above may be amammal, such as a rodent (e.g. a guinea pig, a hamster, a rat, a mouse),murine (e.g. a mouse), canine (e.g. a dog), feline (e.g. a cat), equine(e.g. a horse), a primate, simian (e.g. a monkey or ape), a monkey (e.g.marmoset, baboon, rhesus macaque), an ape (e.g. gorilla, chimpanzee,orangutan, gibbon), or a human. In some preferred embodiments, thesubject is a human. In other embodiments, non-human mammals, especiallymammals that are conventionally used as models for demonstratingtherapeutic efficacy in humans (e.g. murine, primate, porcine, canine,or rabbit animals) may be employed.

In some embodiments, the peptidogenic proteins are chimeric fusionproteins, e.g., a viral protein that has been fused to another protein,that are used for vaccines.

A vaccination strategy can be based on repetitive administration of thepeptidogenic proteins and/or polynucleotides encoding the peptidogenicproteins to the subject as described herein to enable the development ofmemory B cells and memory T cells against the peptidogenic protein.Vaccination can be conducted either prophylactically or therapeutically.The peptidogenic proteins can be derived from either the same startingprotein or from multiple starting proteins. While prophylacticvaccination strategies aim to stimulate the subject's immune system indeveloping preventive adaptive immunity to a pathogen, the goal oftherapeutic vaccination strategy is conducted after the disease has beenalready established or to improve a clinical situation, present in thesubject.

Proteolytic processing involves antigens such as peptidogenic proteinsbeing processed in Antigen Presenting Cells after endocytosis and fusionof the endosome with a lysosome. The endosome then merges with anexocytic vesicle from the Golgi apparatus containing class II MHCmolecules, to which the resultant peptides bind. The MHC-peptide complexthen trafficks to the plasma membrane where the antigen is available fordisplay to CD4⁺ T cells. Any limitation of the proteolytic processing ofthe peptidogenic proteins could promote a narrowing of the diversity ofthe peptide products, which would give the class II MHC molecules feweroptions among which to select stable binding partners, and this couldexacerbate the phenomenon of immunodominant determinants Heightenedimmunodominance would in turn increase the proportion of non-respondersin the population, because immune responsiveness is governed by thegenetics of class II MHC alleles. Hence, vaccines using a mixture ofpeptidogenic proteins and/or polynucleotides encoding the peptidogenicproteins described herein should increase the variety of antigenpeptides resulting from intra-endosomal proteolytic processing andtherefore would be expected to increase the effectiveness of thevaccine.

Introduction into Animals Polynucleotides Encoding Peptidogenic Proteins

Polynucleotides encoding the peptidogenic proteins can also be directlyintroduced into animals. See, for example, U.S. Pat. Nos. 5,676,954;6,875,748; 5,661,133; Sahin et al., Nat Rev Drug Discov, 2014 October;13(10):759-80; Kariko et al., Mol Ther, 2008 November; 16(11):1833-40;Kariko et al., Nucleic Acid Res, 2011, November; 39(21):e142; U.S. Pat.No. 6,511,832. In one example, polynucleotides, such as a DNA sequencesencoding a mixture of peptidogenic proteins are directly injected into ahost animal and the polynucleotides enter into the nucleus to betranscribed to mRNA in order to produce the peptidogenic proteins.

Similarly, the polynucleotides can also be mRNA sequences, such as an invitro transcribed mRNA (IVT mRNA). Essentially, synthetic mRNAs can beengineered to express peptidogenic proteins, and ideally, the mRNA istranslated in the cell's cytoplasm without entering the nucleus. In thecytoplasm, the mRNA is decoded by ribosomes and is translated into thepeptidogenic proteins.

In either method, the peptidogenic proteins are then processed and usedto generate antibodies, much like immunization with a protein. Thepolynucleotides encoding the peptidogenic proteins can be synthesizedusing the genetic codon degeneracy and standard DNA synthesistechniques. Mixtures of different polynucleotides encoding the samepeptidogenic protein, different peptidogenic proteins derived from thesame starting protein, and/or different peptidogenic proteins derivedfrom different starting proteins can be used.

Mammals that can be used to raise antibodies, include but are notlimited to rabbits, rats, mice, llamas, and/or cows. The polynucleotidesdisclosed herein can be injected into the animals via intramuscular,intradermal, intranasal, subcutaneous, intravenous, intratracheal, andintrathecal deliveries. This method of raising antibodies allows for theconcurrent production of many species of antibodies as compared toconventional methodology, substantially increasing the repertoire ofantibodies produced.

Formulations

A pharmaceutical composition may comprise the peptidogenic proteinsdescribed herein, polynucleotides encoding the peptidogenic proteins, oran antibody raised to the peptidogenic protein along with one or morepharmaceutically acceptable carriers, adjuvants, excipients, diluents,fillers, buffers, stabilizers, preservatives, lubricants, or othermaterials well known to those skilled in the art. Suitable materialswill be sterile and pyrogen-free, with a suitable isotonicity andstability. Examples include sterile saline (e.g. 0.9% NaCl), water,dextrose, glycerol, ethanol or the like or combinations thereof. Suchmaterials should be non-toxic and should not interfere with the efficacyof the active compound. The precise nature of the carrier or othermaterial will depend on the route of administration, which may be bybolus, infusion, injection or any other suitable route, as discussedbelow. The composition may further contain auxiliary substances such aswetting agents, emulsifying agents, pH buffering agents or the like.Suitable carriers, excipients, etc. can be found in standardpharmaceutical texts, for example, Remington's Pharmaceutical Sciences,18th edition, Mack Publishing Company, Easton, Pa., 1990.

The term “pharmaceutically acceptable” as used herein pertains tocompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of a subject (e.g., human) without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio. Each carrier,excipient, etc. must also be “acceptable” in the sense of beingcompatible with the other ingredients of the formulation.

In some embodiments, the peptidogenic proteins, the polynucleotidesencoding the peptidogenic proteins or an antibody raised to thepeptidogenic protein may be provided in a lyophilized form forreconstitution prior to administration. For example, lyophilizedreagents may be re-constituted in sterile water and mixed with salineprior to administration to a subject.

Additionally, “cocktails” of the peptidogenic proteins, thepolynucleotides encoding the peptidogenic proteins, or an antibodyraised to the peptidogenic protein are specifically contemplated. Forexample, a mixture of different peptidogenic proteins or polynucleotidesencoding different peptidogenic proteins derived from the same startingprotein can be used to mount an immune response. Alternatively, amixture of different peptidogenic proteins or polynucleotides encodingdifferent peptidogenic proteins derived from different startingmaterials may also be used to mount an immune response.

The formulations may conveniently be presented in unit dosage form andmay be prepared by any methods well known in the art of pharmacy. Suchmethods include the step of bringing into association the activecompound with the carrier which constitutes one or more accessoryingredients. In general, the formulations are prepared by uniformly andintimately bringing into association the active compound with liquidcarriers or finely divided solid carriers or both, and then if necessaryshaping the product.

Formulations may be in the form of liquids, solutions, suspensions,emulsions, elixirs, syrups, tablets, lozenges, granules, powders,capsules, cachets, pills, ampoules, suppositories, pessaries, ointments,gels, pastes, creams, sprays, mists, foams, lotions, oils, boluses,electuaries, or aerosols.

Optionally, other therapeutic or prophylactic agents may be included ina pharmaceutical composition or formulation.

Treatment may be any treatment and therapy, whether of a human or ananimal (e.g. in veterinary applications), in which some desiredtherapeutic effect is achieved, for example, the inhibition or delay ofthe progress of the condition, and includes a reduction in the rate ofprogress, a halt in the rate of progress, amelioration of the condition,cure or remission (whether partial or total) of the condition,preventing, delaying, abating or arresting one or more symptoms and/orsigns of the condition or prolonging survival of a subject or patientbeyond that expected in the absence of treatment.

Treatment as a prophylactic measure (i.e. prophylaxis) is also included.For example, a subject susceptible to or at risk of the occurrence orre-occurrence of the disease may be treated as described herein. Suchtreatment may prevent or delay the occurrence or re-occurrence of thedisease in the subject.

The term “therapeutically-effective amount” as used herein, pertains tothat amount of the peptidogenic protein or an antibody raised to thepeptidogenic protein which is effective for producing some desiredtherapeutic effect, commensurate with a reasonable benefit/risk ratio.

It will be appreciated that appropriate dosages of the peptidogenicprotein or an antibody raised to the peptidogenic protein can vary frompatient to patient. Determining the optimal dosage will generallyinvolve the balancing of the level of therapeutic benefit against anyrisk or deleterious side effects of the administration. The selecteddosage level will depend on a variety of factors including, but notlimited to, the route of administration, the time of administration, therate of excretion of the active compound, other drugs, compounds, and/ormaterials used in combination, and the age, sex, weight, condition,general health, and prior medical history of the patient. The amount ofpeptidogenic protein, polynucleotide encoding the peptidogenic protein,or an antibody raised to the peptidogenic protein and route ofadministration will ultimately be at the discretion of the physician,although generally the dosage will be to achieve concentrations of theactive compound at a site of therapy without causing substantial harmfulor deleterious side-effects.

In general, a suitable dose of the peptidogenic protein or an antibodyraised to the peptidogenic protein is in the range of about 100 μg toabout 250 mg per kilogram body weight of the subject per day. Where thepeptidogenic protein or an antibody raised to the peptidogenic proteinis a salt, an ester, prodrug, or the like, the amount administered iscalculated on the basis of the parent compound and so the actual weightto be used is increased proportionately.

Administration in vivo can be effected in one dose, continuously orintermittently (e.g., in divided doses at appropriate intervals).Methods of determining the most effective means and dosage ofadministration are well known to those of skill in the art and will varywith the formulation used for therapy, the purpose of the therapy, thetarget cell being treated, and the subject being treated. Single ormultiple administrations can be carried out with the dose level andpattern being selected by the physician.

By “simultaneous” administration, it is meant that the peptidogenicproteins, the polynucleotides encoding the peptidogenic proteins, or anantibody raised to the peptidogenic protein are administered to thesubject in a single dose by the same route of administration.

By “separate” administration, it is meant that the peptidogenicproteins, the polynucleotides encoding the peptidogenic proteins, or anantibody raised to the peptidogenic protein are administered to thesubject by two different routes of administration which occur at thesame time. This may occur for example where one agent is administered byinfusion or parenterally and the other is given orally during the courseof the infusion or parenteral administration.

By “sequential” it is meant that the peptidogenic proteins, thepolynucleotides encoding the peptidogenic proteins, or an antibodyraised to the peptidogenic protein are administered at different pointsin time, provided that the activity of the first administered agent ispresent and ongoing in the subject at the time the second agent isadministered. Preferably, a sequential dose will occur such that thesecond of the two agents is administered within 48 hours, preferablywithin 24 hours, such as within 12, 6, 4, 2 or 1 hour(s) of the firstagent.

Multiple doses of the peptidogenic proteins, the polynucleotidesencoding the peptidogenic proteins and/or an antibody raised to thepeptidogenic protein may be administered. For example 2, 3, 4, 5 or morethan 5 doses may be administered after administration of thepeptidogenic proteins, the polynucleotides encoding the peptidogenicproteins, and/or an antibody raised to the peptidogenic protein. Theadministration of the peptidogenic proteins, the polynucleotidesencoding the peptidogenic proteins, and/or an antibody raised to thepeptidogenic protein may continue for sustained periods of time afterinitial administration. For example treatment with the peptidogenicproteins, the polynucleotides encoding the peptidogenic proteins, or anantibody raised to the peptidogenic protein may be continued for atleast 1 week, at least 2 weeks, at least 3 weeks, at least 1 month or atleast 2 months. Treatment with the peptidogenic proteins, thepolynucleotides encoding the peptidogenic proteins, or an antibodyraised to the peptidogenic protein may be continued for as long as isnecessary to achieve a therapeutic response.

The peptidogenic proteins, the polynucleotides encoding the peptidogenicproteins, or an antibody raised to the peptidogenic protein andcompositions comprising these molecules may be administered to a subjectby any convenient route of administration, whethersystemically/peripherally or at the site of desired action, includingbut not limited to, oral (e.g. by ingestion); and parenteral, forexample, by injection, including subcutaneous, intradermal,intramuscular, intravenous, intraarterial, intracardiac, intrathecal,intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal,intratracheal, subcuticular, intraarticular, subarachnoid, andintrasternal; by implant of a depot, for example, subcutaneously orintramuscularly. Usually administration will be by the intravenousroute, although other routes such as intraperitoneal, subcutaneous,transdermal, oral, nasal, intramuscular or other convenient routes arenot excluded.

The pharmaceutical compositions comprising the peptidogenic protein, thepolynucleotides encoding the peptidogenic proteins or an antibody raisedto the peptidogenic protein may be formulated in suitable dosage unitformulations appropriate for the intended route of administration.

Formulations suitable for oral administration (e.g. by ingestion) may bepresented as discrete units such as capsules, cachets or tablets, eachcontaining a predetermined amount of the active compound; as a powder orgranules; as a solution or suspension in an aqueous or non-aqueousliquid; or as an oil-in-water liquid emulsion or a water-in-oil liquidemulsion; as a bolus; as an electuary; or as a paste.

A tablet may be made by conventional means, e.g., compression ormolding, optionally with one or more accessory ingredients. Compressedtablets may be prepared by compressing in a suitable machine the activecompound in a free-flowing form such as a powder or granules, optionallymixed with one or more binders (e.g. povidone, gelatin, acacia,sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers ordiluents (e.g. lactose, microcrystalline cellulose, calcium hydrogenphosphate); lubricants (e.g. magnesium stearate, talc, silica);disintegrants (e.g. sodium starch glycolate, cross-linked povidone,cross-linked sodium carboxymethyl cellulose); surface-active ordispersing or wetting agents (e.g. sodium lauryl sulfate); andpreservatives (e.g. methyl p-hydroxybenzoate, propyl p-hydroxybenzoate,sorbic acid). Molded tablets may be made by molding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may optionally be coated or scored and maybe formulated so as to provide slow or controlled release of the activecompound therein using, for example, hydroxypropylmethyl cellulose invarying proportions to provide the desired release profile. Tablets mayoptionally be provided with an enteric coating, to provide release inparts of the gut other than the stomach.

Formulations suitable for parenteral administration (e.g. by injection,including cutaneous, subcutaneous, intramuscular, intravenous andintradermal), include aqueous and non-aqueous isotonic, pyrogen-free,sterile injection solutions which may contain anti-oxidants, buffers,preservatives, stabilizers, bacteriostats, and solutes which render theformulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents, and liposomes or other microparticulatesystems which are designed to target the compound to blood components orone or more organs. Examples of suitable isotonic vehicles for use insuch formulations include Sodium Chloride Injection, Ringer's Solution,or Lactated Ringer's Injection. Typically, the concentration of theactive compound in the solution is from about 1 ng/ml to about 10 μg/ml,for example from about 10 ng/ml to about 1 μg/ml, from about 1 μg/ml toabout 10 mg/ml, from about 10 μg/ml to about 1 mg/ml, from about 1 mg/mlto about 20 mg/ml, from about 10 mg/ml to about 120 mg/ml, or any otherconcentration suitable for administration of biological drugs (e.g.,proteins, antibodies, etc.). The formulations may be presented inunit-dose or multi-dose sealed containers, for example, ampoules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders,granules, and tablets. Formulations may be in the form of liposomes orother microparticulate systems which are designed to target the activecompound to blood components or one or more organs.

Compositions comprising the peptidogenic proteins, the polynucleotidesencoding the peptidogenic proteins and/or an antibody raised to thepeptidogenic protein may be prepared in the form of a concentrate forsubsequent dilution, or may be in the form of divided doses ready foradministration. Alternatively, the reagents may be provided separatelywithin a kit, for mixing prior to administration to a human or animalsubject.

The peptidogenic proteins, the polynucleotides encoding the peptidogenicproteins, and/or an antibody raised to the peptidogenic protein may beadministered alone or in combination with other treatments, eithersimultaneously or sequentially dependent upon the individualcircumstances. For example, peptidogenic proteins, the polynucleotidesencoding the peptidogenic proteins, or an antibody raised to thepeptidogenic protein as described herein may be administered incombination with one or more additional active compounds.

Various further aspects and embodiments of the present invention will beapparent to those skilled in the art in view of the present disclosure.

It is to be understood that the application discloses all combinationsof any of the above aspects and embodiments described above with eachother, unless the context demands otherwise. Similarly, the applicationdiscloses all combinations of the preferred and/or optional featureseither singly or together with any of the other aspects, unless thecontext demands otherwise.

Modifications of the above embodiments, further embodiments andmodifications thereof will be apparent to the skilled person on readingthis disclosure, and as such these are within the scope of the presentinvention. All documents and sequence database entries mentioned in thisspecification are incorporated herein by reference in their entirety forall purposes. The invention is further described below, with referenceto the following examples.

EXAMPLES Example 1: Generating Peptidogenic Antigens

To generate peptidogenic proteins, a starting protein can be modified atits core residues (e.g., one or more mutations) to alter itsconformational dynamics. Multiple different peptidogenic proteins can bedesigned and expressed to immunize animals, such as rabbits, to generatea polyclonal antibody response. Alternatively, polynucleotides encodingthe peptidogenic proteins can be directly administered to the animals togenerate the peptidogenic proteins in vivo. The response will bemonitored by two complementary and mutually reinforcing methods(Georgiou et al, 2014; FIG. 2): (a) purifying B cells from the blood,spleen, and bone marrow of immunized animals, isolating cDNA from mRNAencoding the variable regions of the heavy and light chains, andanalyzing this repertoire via deep DNA sequencing; and (b)immunoaffinity purifying from immune sera polyclonal Fab or (Fab′)2fragments using antigen attached to a solid support, digesting theeluted Fab/(Fab′)2s with proteases, and sequencing the resultantpeptides using LC/MS/MS.

Specifically, challenging test animals (rabbits) with a variety ofpeptidogenic proteins (or polynucleotides encoding the peptidogenicproteins) where the conformation is similar to the starting protein, butthe conformational dynamics of the peptidogenic protein is varied, canbe performed. Using next-generation DNA sequencing technology, thehumoral response in the animal can be comprehensively characterizedImmunoglobulin V-regions from B lymphocytes can be cloned and subjectedto massively parallel deep sequencing (5-8). In conjunction with this,polyclonal antibodies from the same test animal can be purified byimmunoaffinity chromatography, then protease-digested and subjected toLC-MS/MS to determine the peptide sequences (9, 10). Comparisons ofthese two datasets illuminate the repertoire of individual antibodiescomprising the polyclonal response (9).

For example, small mammalian proteins that have been extremelywell-characterized biophysically can be used as test antigens. Preferredexamples, include, but are not limited to bovine pancreatic trypsininhibitor and/or Alzheimer's amyloid precursor protein Kunitz domain.Alternatively, antigens relevant to unmet vaccine needs, such as forexample, P. falciparum sporozoite antigens can also be generated andtested in this method. Additionally, optimization (or re-optimization)of synthetic vaccines with respect to conformational dynamics of thecomponent proteins (perhaps replacing a single component with acombinatory cocktail of several versions of the same antigen withdifferent core destabilizing mutations) can also be generated. Testingthese new vaccines in clinical trials could involve monitoring of thevaccinated individuals using similar DNA sequence analyses ofblood-derived B-cell V-region repertoires and proteomic characterizationof immunoaffinity-purified polyclonal antibody peptides, similar to theprocedures described above.

Other preferred examples of antigens that can be used according toembodiments of the invention described herein, include, but are notlimited to antigens or antigens derived from, malarial polypeptides suchas thrombospondin-related adhesive protein (TRAP) and/or apical membraneantigen 1 (AMA1), human immunodeficiency virus (HIV) gp120 and gp41,hepatitis C (HCV) envelope glycoproteins E1 and E2, Middle Eastrespiratory syndrome coronavirus (MERS-CoV) Spike glycoprotein, humaninfluenza virus hemagglutinin (HA) and neuraminidase, hepatitis B virus(HBV) capsid core, as well as antigens from related viruses that infectapes, monkeys, birds, pigs, camels, and other animals.

In preferred embodiments, any one of the P. falciparum protein antigenslisted in the following Table 2 can be used as a starting protein toderive the peptidogenic protein. Additionally, multiple antigens listedin Table 2 can be used as the starting proteins to derive multipledifferent peptidogenic proteins to be used as a vaccine, generate animmune response, including the raising of antibodies.

TABLE 2 Predicted Predicted SP SP Predicted Cleavage Predicted CleavageGene Size Paralogs Site Gene Size Paralogs Site MAL13P1.225 157 23/24PFI0880C 396 25/26 PF13_0203 158 22/23 PF11_0251 421 22/23 PF11_0164 195PFC0795C 21/22 PFC0065C 437 PF08_0022, 31/32 PF14_0015 PFL0375W 20916/17 PFC0925W 492 30/31 PFI1270W 217 20/21 MAL13P1.121 565 34/35PF10_0104 223 22/23 PF13_0133 590 33/34 PF13_0128 230 18/19 PFL2015W 67627/28 PF11_0058 233 35/36 PFD0440W 693 25/26 PFA0490W 234 29/30 PFC0330W699 26/27 PF07_0087 244 26/27 PFD0430C 840 24/25 PFB0570W 250 21/22PF14_0462 851 PFC0550W 28/29 PF13_0180 258 PFL0740C 19/20 PF07_0100 103235/36 PF11_0065 282 23/24 MAL7P1.23 1183 30/31 PF14_0678 287 21/22PFL1835W 1188 26/27 PF13_0125 292 19/20 PF07_0047 1229 PFF0940C 35/36PF13_0141 316 PFF0895W 20/21 PF14_0250 1320 28/29 PF14_0117 327PFI1775W, 22/23 PFE0905W 1379 24/25 PFL2530W PF11_0098 343 26/27PFA0180W 1472 31/32 PF14_0660 358 23/24 PFL1210W 1696 25/26 PFD0240C 37820/21 PF14_0363 1922 26/27 PFE0080C 398 21/22 PFB0400W 2508 34/35PFA0660W 402 PFB0090C, 34/35 PFI0920C 577 26/27 PFB0595W, PFE0055CPF11_0352 423 23/24 PF14_0094 768 22/23 PF11_0055 424 21/22 PFA0125C1567 26/27 PFB0475C 446 22/23 PF10_0372 120 25/26 PF11_0302 452 21/22PFL2315C 137 28/29 PFA0210C 466 23/24 MAL13P1.271 181 36/37 PF07_0089467 16/17 MAL7P1.31 236 20/21 PF14_0060 475 16/17 PF10_0317 263PF14_0653 35/36 MAL8P1.17 483 24/25 PF07_0070 322 19/20 MAL7P1.77 52223/24 MAL7P1.64 357 28/29 PF11_0099 540 33/34 PFI0935W 370 21/22PF07_0068 546 22/23 PFA0160C 434 22/23 PF13_0201 574 25/26 PFB0465C 45727/28 PF07_0094 579 17/18 PF10_0208 627 23/24 PF07_0006 594 MAL8P1.14322/23 PFB0760W 686 25/26 PFL0770W 618 PF07_0073 20/21 MAL13P1.206 68726/27 PFI1645C 642 PF13_0262 18/19 PF14_0541 717 15/16 PF14_0166 67425/26 PFL0790W 870 21/22 PFE0815W 681 24/25 PFL2410W 1039 24/25PF11_0174 700 27/28 PF14_0440 1191 23/24 PFE0475W 722 PFB0525W 21/22PF11_0333 1503 25/26 PF11_0074 743 17/18 PF10_0242 1541 20/21 PFL1385C743 23/24 PFC0590C 1816 20/21 PF14_0102 782 22/23 PF14_0342 1898 27/28PF11_0212 791 20/21 MAL7P1.92 2543 PFI0550W 22/23 PF07_0129 811 21/22PF14_0593 1357 18/19 PFL2570W 816 22/23 MAL13P1.49 144 24/25 PFL1070C821 28/29 MAL13P1.172 260 26/27 PFB0695C 888 32/33 PF08_0006 272 19/20PF11_0175 906 PF08_0063 26/27 PFD1035W 328 37/38 MAL13P1.22 912 15/16PF11_0052 336 24/25 PFL0035C 926 27/28 MAL13P1.79 383 19/20 PFI0685W 95518/19 PF10_0295 426 23/24 PFD0425W 984 21/22 PFL1745C 459 22/23PF14_0293 992 24/25 PF14_0677 467 24/25 PF14_0344 993 20/21 PFL0600W 55823/24 PFL0560C 1024 20/21 PF08_0108 573 PF14_0281 26/27 PF07_0035 124820/21 PF08_0081 577 18/19 PFL1675C 1256 21/22 PF14_0620 858 25/26PFC0435W 1294 19/20 PFE0710W 867 21/22 PFI1445W 1364 19/20 PF11_02701013 20/21 PF13_0354 1408 23/24 MAL7P1.149 1051 19/20 PFC0110W 1416MAL7P1.229, 24/25 PFC0810C 1119 22/23 PFA0125C, PFD1155W PFC0120W 141724/25 PF14_0249 1169 25/26 PF08_0078 1419 20/21 PF13_0116 1258 19/20PF14_0614 1502 16/17 MAL13P1.60 1260 25/26 PF14_0051 1515 26/27PF11_0246 1336 23/24 PF11_0076 1988 22/23 PFL2505C 2215 21/22MAL13P1.262 2006 21/22 PFB0405W 3135 20/21 PFC0640W 2114 26/27 PF11_0256608 17/18 PFL2520W 2792 MAL13P1.176, 24/25 PF08_0047 613 28/29 PF13_0198PFC0282W 116 23/24 PFC0835C 440 22/23 PF08_0004 137 25/26 PFI0605C 44620/21 PF11_0224 162 22/23 PF10_0127 499 16/17 PF13_0272 208 22/23PF11_0344 622 24/25 MAL13P1.171 211 20/21 PF10_0130 628 25/26 PFE1340W214 27/28 PFL2395C 639 PF14_0428 28/29 PF14_0369 235 20/21 PF08_0008 73821/22 PF14_0178 259 22/23 PF14_0201 966 22/23 PFL0870W 352 24/25PFI1475W 1720 19/20 PFC0210C 397 18/19 PF13_0182 1838 26/27 PFI0500W 43228/29 PF14_0495 2189 20/21 PF11_0069 276 25/26 PF13_0277 2068 22/23PFD0355C 286 32/33

To alter the conformational dynamics of a starting protein, thefollowing changes in Gibbs Free Energy, shown in Table 3 below, can beconsidered:

TABLE 3 Amino Acid Substitution Average Gibbs Free Energy difference(multiple positions in between mutant and wild type at core variousproteins) residues within a protein ΔΔG (kJ/mol) Val −> Ala −12.1(±3.3)Val −> Thr −11.3(±3.7) Val −> Asn −21.5(±1.0) Leu −> Ala −14.2(±4.2)

As discussed in Loladze et al (J. Mol. Biol. 320, 343-357 (2002)), thefollowing amino acid substitutions can decrease the thermodynamicstability (e.g., reflected in the Gibbs free energy) and alter theconformational dynamics of a starting protein. For example, Val and Leu(and other larger non-polar amino acid residues) can be substituted withsmaller ones such as Ala, Thr, Asn, and/or Gly. In addition, the buriedsite of Glu in the starting protein, can be substituted with Leu, Val,Asn, Thr, Ser, Ala, and/or Gly. These single site amino acidsubstitutions are expected to generate peptidogenic proteins with lowerstability but a similar conformation to the starting protein.

Alternatively, the conformational dynamics of the starting protein isaltered by replacing (a) at least one threonine with a valine, alanine,glycine or serine; or (b) at least one cysteine with alanine, valine,glycine, serine or threonine; or (c) at least one valine with alanine,glycine, leucine or isoleucine; or (d) at least one leucine withalanine, valine, glycine, or isoleucine; or (e) at least one isoleucinewith alanine, valine, leucine, or glycine; or (f) at least one proline,methionine, phenylalanine, tyrosine, or tryptophan with alanine, valine,leucine, isoleucine, or glycine; or (g) at least one aspartic acid orasparagine with glycine, serine, threonine, alanine, valine, leucine,isoleucine; or (h) at least one glutamic acid or glutamine with asparticacid, asparagine, glycine, serine, threonine, alanine, valine, leucine,or isoleucine; or (i) at least one lysine with arginine, histidine,glycine, serine, threonine, alanine, valine, methionine, leucine, orisoleucine; or (j) at least one arginine with lysine, histidine,glycine, serine, threonine, alanine, valine, methionine, leucine, orisoleucine; or (k) at least one histidine with lysine, arginine,glycine, serine, threonine, alanine, valine, glutamine, asparagine,leucine, or isoleucine; or (l) at least one alanine with a glycine; or(m) at least one residue with a non-natural amino acid; and/or (n) anyof the above combinations.

In still further preferred embodiments, the conformational dynamics ofthe starting protein is altered by replacing: (a) at least onetryptophan with tyrosine, phenylalanine, methionine, histidine,isoleucine, leucine, valine, alanine or glycine; or (b) at least onetyrosine with phenylalanine, methionine, histidine, isoleucine, leucine,valine, alanine or glycine; or (c) at least one phenylalanine withtyrosine, methionine, histidine, isoleucine, leucine, valine, alanine orglycine; or (d) at least one proline with methionine, leucine,isoleucine, valine, alanine, or glycine; or (e) at least one histidinewith phenylalanine, tyrosine, methionine, isoleucine, leucine, valine,alanine, glycine, lysine, arginine, serine, threonine, asparagine, orglutamine; or (f) at least one methionine with isoleucine, leucine,valine, alanine or glycine; or (g) at least one isoleucine with leucine,valine, alanine or glycine; or (h) at least one leucine with isoleucine,valine, alanine or glycine; or (i) at least one valine with alanine,glycine, leucine, or isoleucine; or (j) at least one cysteine withalanine, valine, glycine, serine or threonine; or (k) at least oneaspartic acid with glutamic acid, glutamine, asparagine, glycine,serine, threonine, alanine, valine, leucine, or isoleucine; or (l) atleast one glutamic acid with aspartic acid, glutamine, asparagine,glycine, serine, threonine, alanine, valine, leucine, or isoleucine; or(m) at least one alanine with a glycine or proline; or (n) at least oneserine with alanine or glycine; or (o) at least one glycine with alanineor proline; or (p) at least one lysine with arginine, histidine,glycine, serine, threonine, alanine, valine, methionine, leucine orisoleucine; or (q) at least one asparagine with glycine, alanine,serine, threonine, valine, leucine, isoleucine, glutamine, aspartic acidor glutamic acid; or (r) at least one glutamine with glycine, alanine,serine, threonine, valine, leucine, isoleucine, glutamine, asparticacid, glutamic acid, or histidine; or (s) at least one arginine withlysine, histidine, glycine, serine, threonine, alanine valine,methionine, leucine, or isoleucine; or (t) at least one threonine withvaline, alanine, glycine or serine; or (u) a hydrophobic residue with asmaller, similar hydrophobic residue; or (v) at least one residue with anon-natural amino acid; or (w) any of the above combinations. Acombinatorial approach may be used to determine optimal substitutions toincrease immunogenicity.

Example 2: Peptidogenic Proteins of Bovine Pancreatic Trypsin Inhibitor

Bovine pancreatic trypsin inhibitor (BPTI) is an extremelywell-characterized small protein, on which there is a substantial bodyof literature describing its folding, structure, activity, thermodynamicproperties, expression properties, and protease specificities (15). Ourown lab was the first to express recombinant BPTI and engineer itsproperties using site-directed mutagenesis (16, 17). Wild type BPTI hasthree disulfide bonds, cross-linking disulfides 14-38, 30-51, and 5-55;the 14-38 disulfide is on the surface, and the other two disulfides aredeeply buried in the hydrophobic core of the protein. Mutations of anyone of these disulfides by replacing the two disulfide cysteines withalanine residues destabilizes the BPTI molecule (18). All possiblecombinations of disulfide bond mutants of BPTI have been made byourselves and by others, and all are markedly destabilizing.Importantly, where it has been examined, for all combinations of mutantsof BPTI that knock out one or two native disulfide bonds, the proteinnevertheless maintains a similar three-dimensional structure and trypsininhibitor activity comparable to wild type BPTI (19-22) Therefore,despite stability differences manifested by Tms ranging from >100° C. to<40° C., the wild type molecule and its disulfide mutants all displaysimilar, if not virtually identical 3D conformational epitopes. Forexample, at 40° C. the mutant protein would be almost 50% unfolded atbody temperature, and at >100° C. (higher than the boiling point ofwater) the wild type protein is among the most thermostable proteinsknown.

TABLE 4Mutants of BPTI that knock out one or more of the native disulfidebonds or core residues while preserving 3D structure BPTI variantSequence wild type RPDFC LEPPY TGPCK ARIIR YFYNA KAGLC QTFVY GGCRAKRNNF KSAED CMRTC GGA (SEQ ID NO.: 919) [C14A C38A]RPDFC LEPPY TGPAK ARIIR YFYNA KAGLC QTFVY GGARAKRNNF KSAED CMRTC GGA (SEQ ID NO.: 920) [C14A, C38A],RPDFC LEPPY TGPAA ARIIR YFYNA KAGLC QTFVY GGARA K15AKRNNF KSAED CMRTC GGA (SEQ ID NO.: 921) [C14A, C38A],RPDFC LEPPY TGPAA ARIIR YAYNA KAGLC QTFVY GGARA K15A, F22AKRNNF KSAED CMRTC GGA (SEQ ID NO.: 922) [C14A, C38A],RPDFC LEPPY TGPAA ARIIR YFANA KAGLC QTFVY GGARA K15A, Y23AKRNNF KSAED CMRTC GGA (SEQ ID NO.: 923) [C14A, C38A],RPDFC LEPPY TGPAA ARIIR YFYNA KAGLC QTFVY GGARA K15A, N43GKRGNF KSAED CMRTC GGA (SEQ ID NO.: 924) [C14A, C38A],RPDFC LEPPY TGPAA ARIIR YFYNA KAGLC QTFVY GGARA K15A, F45AKRNNA KSAED CMRTC GGA (SEQ ID NO.: 925)

For our immunological experiments with BPTI, since we are interested inprotease digestion and peptide generation in vivo from the antigen, wewill make the BPTI mutants described in Table 4. Mutated residues areunderlined, cysteine residues are shown in bold. These consist of wildtype BPTI with the surface disulfides 14-38 mutated to alanine, whichhas been shown to confer increased stability to reducing agents. TheBPTI mutants will also be made in the [Lys15→Ala] background. TheLys15-Ala mutation ablates the P1 residue side chain and reduces BPTI'saffinity towards trypsin and other proteases by as much as 107-fold,rendering it essentially inactive as a protease inhibitor (23).Additional mutations within the core of the protein (e.g. F22A, Y23A,N43G, F45A) serve to destabilize the protein and alter conformationaldynamics to varying degrees while still maintaining a 3D structurecomparable to wild type BPTI. This table is intended to be non-limitingwith respect to present invention embodiments.

Analogous mutations can be made in the Alzheimer's amyloid precursorprotein Kunitz inhibitor (APP-KI), which is a human protease inhibitorhomologous to BPTI. APP-KI has a relatively low isoelectric point (pI)and so, unlike BPTI, it should be electrostatically nearly neutral incharge at lysosomal pH. Like BPTI, APP-KI has previously been expressedand characterized in terms of folding, activity, and 3D structure, andit has three disulfide bonds precisely homologous to those found inBPTI.

We will express the mutants both with and without flanking tagsequences. Tags we have used to vary solubility include the calmodulinbinding peptide (CBP) tag, which is highly soluble, to the TrpLE tag,which is highly insoluble (24). In a particularly favored construct,however, we use a tripartite tag: AviTag-hexaHis-TEV protease cleavagesite. This tag confers intermediate solubility, can by biotinylatedusing the BirA biotin ligase (25), allows binding to a HisTrap columnfor purification and/or on-column refolding (Campbell and Anderson, inpreparation), and can be cleaved off the antigen if necessary. Theantigen can be used to immunize animals either without the tag (i.e.,after TEV cleavage) or with the tag intact followed by subtractivedepletion of anti-tag antibodies (S. Blackshaw and D. Eichinger,personal communication).

Example 3: Preferred Targets of the Present Invention

As used herein a “Target” is a specifically selected protein disclosedin Table 5 that can be modified to have an improved peptidogenicity asdescribed herein. Column 1 lists the SEQ ID NO. corresponding to thesequence provided in the Sequence Listing. Column 2 lists the “ProteinName” of each Target and Column 3 provides the “UniProt ReferenceNumber” which is a unique “cataloging” number (UniProt Reference Numbersprovide a mapping of a proteome to a reference genome assembly, e.g., asproduced by the Genome Reference Consortium (GRC)) used in the art thatprovides publicly known and established descriptions of both thefunction, expression and sequence information for each Target listed inColumn 2. This public information (retrieved from the UniProt database(http://www.uniprot.org) on Aug. 10, 2016) including the sequenceinformation corresponding to each Target, is herein incorporated byreference in its entirety. The Sequence Listing and Table 5 describesthe positions of the specific residues in each target protein wheremutations can be made to generate the corresponding peptidogenicproteins along with the specific amino acids that can be substituted ateach position. In preferred embodiments, multiple substitutions can bemade in each target protein at the recited positions in the SequenceListing and as shown in Table 5. In further preferred embodiments, atleast 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more of the residues listed inthe Sequence Listing and/or Table 5 for each target protein, in anycombination, can be changed in the respective starting Target proteinslisted in Column 2 using the amino acid specified in the SequenceListing and/or as described in the last two paragraphs of Example 1. Byspreading the mutations over multiple positions and/or target proteins,and by mixing these mutated molecules together, an immunization cocktailcan be created.

TABLE 5 TARGETS Exemplified Sites of Mutations to Generate PeptidogenicProtein SEQ ID NO. Protein Name/Strain UniProt ID No. (Each position canbe substituted alone or in any combination with any of the other listedamino acid positions.) 1 Hemagglutinin [Cleaved into: HemagglutininA4GCL9 V7, I20, C21, I22, A26, V33, V36, V43, L49, L50, L58, C59, L61,L67, L69, C72, I74, A75, W77, L78, L79, C84, L87, W93, HA1 chain;Hemagglutinin HA2 chain]/strain Y95, I96, V97, Y108, L118, L122, V125,F128, F134, A151, A152, C153, H155, L165, L166, W167, L168, L178, V190,A/USA: Phila/1935 H1N1 L191, V192, L193, W194, V196, H197, H198, Y209,Y215, V216, V218, V219, Y223, M244, Y246, Y247, L250, L251, I257, F259,A261, L265, I266, A267, Y270, A271, F272, A273, L274, F278, I282, I283,C292, C296, A302, I303, H313, I317, V324, L329, M331, V332, A349, M361,Y366, A388, I389, A440, L452, V459, L462, V466, L470, C481, H486, C488,C492, M493 2 Proprotein convertase subtilisin/kexin A8T655 V80, A95,L98, A102, F122, V124, A134, I143 type 9 (EC 3.4.21.—) 3 Plasminogen (EC3.4.21.7) B2R7F8 Y193, W209, C234, W244, C245, F246, C257, I259 4 cDNAFLJ60453, highly similar to B4DEZ9 V80, L98, A102, F122, V124, A134,I143 Proprotein convertase subtilisin/kexin type 9 (EC 3.4.21.—) 5Receptor protein-tyrosine kinase B4DTR1 V474, I476, A495, I512, C513,V521, L530, V534, L546, L547, W549, C550, I553, A554, M557, L560, L565,V566, (EC 2.7.10.1) H567, L570, A571, A572, V575, V577, V583, I585,A591, A614, F623, V629, W630, Y632, V634, V636, L639, M640, I655, L659,I670, V675, M679, C682, W683, F693, F700, M703, V711 6 Interleukin-4D4HNR6 L31, I34, L38, C48, C70, A72, A73, L76, C89, H100, L107, L110,L114, A118, L133, F136, L140, M144 7 Cell wall-binding repeatprotein/NAP07 D5RWT1 F32, F51, F53, F73, A74, F104, F124, A129, A132,F143, F164, A165, F195, F215, A220, A223, F237 8 Insulin, isoform 2F8WCM5 L35, A38, L39 9 Fusion glycoprotein F0 G8EJ09 L204, I206, I214,S215, I233, V247, M251, L257, I261, M274, I280, V281, Y299, V301, L303,C313, C333, C343, V349, F352, V365, F366, C367, C382, A412, I413, V414,C416, C422, A424, V442, V450 10 TcdA I6YE93 F2585, A2593, F2604, F2625,A2626, F2656, F2676, A2681, A2684, F2698 11 Spike glycoprotein/isolateK9N5Q8 C30, F40, W44, I48, A53, Y58, Y64, I67, L74, Y85, F101, Y105,F112, V117, I120, A123, A124, I132, Y144, V153, L169, UnitedKingdom/H123990006/2012 (HCoV-EMC) V170, L172, C176, A182, Y184, C185,C195, F232, C237, F239, Y243, W253, F254, I256, V263, L265, M278, F279,A282, I290, Y292, Y293, I300, A309, A312, F313, Y314, Y316, L318, V329,A336, C339, L347, C349, Y351, F354, V360, Y361, F366, A368, C383, F404,C407, Y409, L411, L414, L415, L417, V420, F423, C425, A434, C437, Y438,F446, A461, I464, F467, Y469, C478, A482, Y497, C503, I573, Y577, V584,C585, C603, Y606, V616, F617, C620, V631, Y632, Y648, Y649, C650, C654,V655, V657, V659, V661, I662, Y663, A671, L673, V677, C679, L697, L707,V711, C713, V724, C727, L729, L731, L735, C736, A737, V770, I782, F786,I795, V802, C806, V810, C811, C817, L821, Y824, F827, C828, L835, L893,L894, F895, V898, Y909, C912, L923, C925, V934, L935, Y947, W960, A968,F972, Y978, V989, L990, I997, F1001, A1004, A1007, F1012, A1018, V1026,A1030, A1032, L1033, L1036, L1040, F1044, A1046, I1047, A1049, I1054,L1058, A1065, I1067, L1070, I1071, L1075, L1078, A1080, L1086, V1103,C1106, V1107, F1116, C1117, I1123, V1127, A1130, L1134, F1136, Y1141,L1155, C1156, A1166, Y1171, F1172, W1184, Y1192, I1197, V1209, Y1211,L1223, L1260, L1262, M1266, L1276, Y1280, I1281, C1320, C1323, C1327 12Serine/threonine-protein kinase Sgk1 O00141 A115, V126, F158, F166,L172, F174, V175, L184, A199, Y202, A203, A204, I206, A207, A209, L210,L223, I228, L230, (EC 2.7.11.1) I236, L238, A265, V278, W280, W281,C282, L283, A285, V286, L287, M290, A324, L327, L328, L331, I349, F355,L363 13 AP-4 complex subunit mu-1 O00189 V187, L189, V191, L195, I199,V210, I214, L216, M226, I228, L230, F234, V250, L270, V281, M282, Y284,L286, F296, L311, V313, L315, L317, C319, A327, V330, L332, L334, L347,W363, L365, V368, M380, A405, L407, F409, L411, L419, Y449 14 Toll-likereceptor 4 O00206 Y38, C40, L59, L61, L69, F74, F77, L80, L83, L85, C88,I90, I93, A97, Y98, L101, L104, L107, L109, I114, A121, F122, L125,L128, L131, A133, L141, I146, L149, L152, L155, V157, A158, I162, F165,L167, F171, L174, L177, L180, L182, I187, I190, L195, V197, L198, L203,L206, L208, L210, M215, I218, A222, F223, I226, L228, L231, L233, M243,C246, I247, L253, V255, L258, L260, F272, A276, L277, L280, F288, L290,Y296, L297, I300, L303, F304, L307, V310, F313, L315, V318, I320, V323,F326, F330, W332, L335, L337, C340, F342, L348, L350, L353, L356, F358,G363, L372, L375, L378, L380, L385, F387, C390, C391, F396, L401, L404,L406, I412, M414, F418, L421, L424, L427, F429, M437, V442, F443, L446,L449, I450, L452, I454, V461, I466, F467, L470, L473, L476, M478, F483,L488, F492, L495, L498, L501, L503, C506, L508, A515, F516, L519, L522,V524, L525, M527, F532, F533, L535, Y540, L543, L546, L549, Y551, I556,L571, L574, L576, F581, F590, L591, I594, L600, M607, V620 15 Tumornecrosis factor receptor superfamily O00220 C132 member 10A 16Agouti-related protein O00253 C94, C119 17 Tubby-related protein 1O00294 V295, C307, L309, L326, L337, I352, I367, L370, V381, F382, L403,A404, A405, V406, V423, I424, I425, I437, L446, L461, I493, V503, L504,F506, F514, L516, Y518, L522, C523, A524, L525, A527, F528, A529, I530,A531, L532, L539 18 Tumor necrosis factor receptor superfamily O00300C41, C44, C65, C124 member 11B 19 Krev interaction trapped protein 1O00522 A10, V12, A13, V14, I15, Y28, Y33, I35, L36, L37, L54, I68, V72,A108, L110, I112, V113, L135, L152, M156, L157, L160, L164, I174, L292,H293, A296, L304, A323, I325, H326, A328, C329, A336, L340, C346, A362,A363, I370, V371, L374, C396, A407, I424, V434, V444, I447, I463, I465,W487, L491, L508, I522, A527, I528, I530, L531, A535, L539, A546, L551,I552, L554, A555, L557, L558, L559, H571, I584, V585, L590, A594, I601,Y605, L621, F625, L626, C629, I632, V658, V660, V662, L667, H668, L669,L670, F697, I699, V710, A715, V718, L722, L725 20 C-C motif chemokine 21O00585 L63, F64, C75, A76, V83 21 Lysosomal alpha-mannosidase O00754A241, Y306 22 Receptor-type tyrosine-protein phosphatase T O14522 F74,M75, V77, A88, L90, L92, H101, F105, L120, V122, V124, V135, A149, L151,A152, I153, Y161, V163, F165, I177, A178, V179, V184, F211, C213, L227,A250, V252, Y265, C267, V268, I269, V277, A281, L305, I307, V325, I358,L362, L403, L405, C417, V424, L449, I458, L460, L462, L464, I502, I504,Y519, I521, F553, Y562, F564, I566, A568, V578 23 Tumor necrosis factorreceptor superfamily O14763 C81, C139 member 10B 24Tripeptidyl-peptidase 1 O14773 L49, F51, A52, L61, V65, L80, L82, V85,A86, V89, V99, A105, F119, C122, L124, I126, A129, L133, F138, V150,Y157, L159, V167, F169, V170, L173, V200, Y209, A226, C227, A228, F230,L240, F243, V277, Y279, L280, M281, A283, A285, I287, F304, L305, W307,L308, V320, H321, V323, Y336, I337, V340, L344, A347, A348, A349, L355,F356, A363, F378, A380, V385, V388, F397, V404, V426, A448, V452, A453,A454, L455, Y459, V461, V462, V471, A476, V480, F481, I484, L485, L487,I488, V518, H523, C526, F536, V545, L556, L560 25 Tumor necrosis factorligand superfamily O14788 L168, I170, L184, L206, V208, Y214, L216,A218, I220, F222, L238, V240, V242, L283, I289, I291, V293, A310 member11 26 Growth/differentiation factor 8 O14793 C281, C282, C372, C374 27Ras-related protein M-Ras O14807 L11, Y14, L16, V17, V18, V19, V24, L29,F33, V39, I56, A61, I62, L63, V65, L66, A69, M77, M82, F88, L89, I90,V91, Y92, V94, V103, F106, I110, V113, F119, M121, I122, L123, V124,A125, I136, A145, A157, V164, A167, F168, L171, V172 28 Tumor necrosisfactor O14836 C89, C100, A101 receptor superfamily member 13B 29Interferon regulatory factor 6 O14896 W449 30 Natural cytotoxicitytriggering receptor 3 O14931 A35, L37, C39, A49, F56, H89, A91, I95,V98, I105, Y106, C108, V110, V112, L125 31 Peripheral plasma membraneprotein CASK O14936 F8, C15, V26, C29, V40, V45, F48, L59, L69, I74,L77, L87, M89, V90, F91, L99, C100, I103, Y113, A118, M122, I125, L126,A128, L129, C132, I137, I138, H139, V142, C146, V147, L148, L149, V158,L160, A166, A187, V191, V202, W203, C205, V207, I208, L209, F210, I211,L212, L213, F227, I230, W242, A249, L252, V253, M256, V267, A270, W275,L276, L295, A310, V312 32 Cyclin-G-associated kinase O14976 L40, V42,A57, L68, L71, I82, L92, I98, I107, L122, L130, C145, V148, L149, I151,F152, C156, A158, V159, M162, (EC 2.7.11.1) H171, L179, L181, I187,L189, F192, I198, I246, L249, L253, L256, F288, I292, M295, V309, L313,A317, I328, F525, V640 33 Synapsin-3 O14994 L94, L95, V96, I97, W104,F126, C139, V141, I162, L163, V164, V181, V192, L211, F223, V226, V246,V247, V261, F267, V273, V274, A281, I295, A304, Y305, W335, V336, C339,I348, C349, A350, V351, A353, I363, M371, M385, A386, V389 34 Spectrinbeta chain, non-erythrocytic 2 015020 F63, W66, V67, L71, L81, L85, L91,L92, L94, L95, V119, A122, L123, L126, L133, I141, V142, L152, V153,I156, I157, I162, I165, L182, C186, V198, F201, W205, A210, F211, A213,I214, V215, L228, H234, L237, A240, F241, A244, L253, L254, V259, I269,I270, Y272, V273, A274, Y276, Y277, L2225, A2238, V2246, C2248, L2250,L2255, F2257, L2278, V2295, F2296, L2298, F2308, A2310, W2319, V2323,A2326 35 Niemann-Pick C1 protein O15118 W27, V59, C63, L73, C74, C75,L80, L94, C97, C100, L104, L107, C113, L121, V141, L144, Y146, V148,F152, A153, M156, A159, C160, V163, A172, L173, C177, W189, I190, F194,C227, C243, L408, I410, F431, L435, V443, L444, L446, I450, V462, L464,I467, C479, I481, V484, L485, Y487, F488, L495, A507, H510, H512, C516,C533, V541, L545, V546, L547, A558, L561, I563, F565, V567, A580, W583,F587, L649, L656, A659, L720, L724, V727, F763, A1035, F1100, A1124,M1138, M1228 36 Laminin subunit alpha-5 O15230 L273 37Phosphomannomutase 2 O15305 L8, C9, L10, F11, L17, M28, F31, L32, L35,I41, V43, V44, V52, L56, V60, Y64, V67, F68, L73, A75, I87, L99, C103,M126, L127, V129, I132, F144, F157, L161, I178, F180, V182, C192, L193,V196, F206, F207, I220, C241 38 Phosphatidylinositol 3,4,5- O15357 A31,L34, L35, F44, L45, V46, A55, L58, C59, V60, I71, V81, V87, L98, I99,Y102, L113, V117, I424, V426, F427, I428, trisphosphate 5-phosphataseW431, I466, V468, F469, L489, I508, V510, A511, V512, L513, V514, A543,V544, V546, F548, F550, F555, F557, C560, 2 (EC 3.1.3.86) H601, F603,F605, L608, Y610, I619, L631, L637, V646, F657, W688, C689, I692, L693,Y707, C709, I713, V721, F722, V727, M1201, L1205, L1217, L1228, L1236,V1241, L1250 39 Eukaryotic translation O15372 V36, V39, V45, L67, I78initiation factor 3 subunit H 40 Neural cell adhesion molecule 2 O15394L32, F40, C42, A44, W53, L78, I80, A83, C93, A95, V107, A132, V134,C136, I173, I176, Y184, C186, V190, I201, V203, V205, A220, A222, F230,C232, W244, L266, V268, I271, Y279, C281, A283, A294, L296, I304, L320,C322, W334, F343, I354, L365, I367, V370, Y378, C380, A382, M393, I418,I420, C422, V424, W434, L460, I462, Y473, C475, A477, Y488, A493, A512,V514, F516, Y530, V532, L556, I567, V569, A570, A571, L611, I613, A621,V628, L653, L656, V664, I666, A668 41 Toll-like receptor 3 O15455 A35,C37, I53, L56, L58, L63, L66, F71, Y74, L77, L80, V82, I87, L98, L101,V103, L104, L106, L111, F119, L125, L128, L130, I135, F143, L149, L152,L154, L164, L170, L173, L176, L178, I183, L186, L191, I193, F194, L199,L202, L204, I209, C216, F217, L223, L226, L228, V231, L241, C242, L245,I250, L253, L255, L260, F268, L269, L271, L276, L279, L281, L286, V289,F294, L297, L300, F303, L305, I310, L313, L318, L321, V324, L327, L329,F351, L354, L357, L360, M362, F375, L378, L381, L384, L386, L396, F401,L404, L409, H410, L412, L414, I419, I422, A426, F427, L430, L433, L436,L438, L440, I443, L447, W452, L455, I458, I461, L463, L469, L471, F476,V479, L482, L485, L487, V490, L492, V495, F502, L505, L508, L511, L513,I521, M525, L526, L529, L532, L535, L537, L542, L545, W546, F557, L558,L561, L564, L567, L569, F574, F582, L585, L588, I591, L593, L595, L598,L601, F606, L612, L615, L617, I622, V625, A633, F634, L640, M642, F647,I654, F657, Y675, V688 42 Fibroblast growth factor 10 O15520 L82, L90,I92, L111, I113, V123, A125, L132, A133, M134, C150, L152, Y164, M176,V178, A179, L180, A199, F201 43 Leucine-rich repeat transmembraneprotein O43155 I75, L100, I121, L129, L132, L135, L138, L140, I159,L161, L163, L164, L166, L185, A193, L203, L206, L209, V211, FLRT2 L215,L216, F235, I237, L254, L257, L259, L278, L281, L288, L291, F296, L299,L305, I318, L325 44 Kunitz-type protease inhibitor 2 O43291 C84, C133,C179 45 Desert hedgehog protein O43323 A59, V67, A95, M99, C103, V107,L110, A111, V114, L123, V125, W129, L140, H141, A146, L147, I149, Y159,L161, L162, A163, A166, V174, V182, V184, V186, A188, V194 46 Glutamatereceptor ionotropic, delta-2 O43424 V445, V446, F453, V454, F470, V474,L475, L478, A491, L508, V509, A517, I519, I521, L524, V534, V547, L548,L549, L562, L671, Y679, M708, I712, V732, A738, F739, V740, V745, L746,F758, Y770, I772, A773, L774, F784, I788, M797 47 Tumor necrosis factorligand superfamily O43557 A96, L98, L112, A132, L133, V135, Y141, I143,V147, L149, I162, H164, L166, L180, V215, V216, V217, L224, F235 member14 48 Carbonic anhydrase 12 (EC 4.2.1.1) O43570 W43, I58, L60, Y79, L89,V96, L98, M104, I106, L118, L120, H121, W122, H133, A142, L144, H145,I146, H148, A160, A168, L170, A171, V172, L173, I174, Y183, I186, L190,V193, V202, I207, L210, C230, V234, W236, V238, F239, I245, L250, L251,L253, A256, L257, M270, V285 49 Alpha-actinin-4 O43707 F56, W59, C60,L64, F78, L82, L84, L87, L88, V112, A115, L116, I119, L126, A131, I134,V135, L143, M145, I146, I149, I150, A154, I155, I158, L169, C173, V185,F188, W192, A197, F198, A200, L201, I202, L215, V221, L224, A227, F228,A231, M240, A243, I246, A256, I257, M258, Y260, V261, F264, Y265, A274,A415, F418, A422, L436, I449, I473, L480, V491, I498, L505, L516, H530,Y533, A537, M544, I563, L577, I587, A594, L605, I619, V626, L637, M679,I719, I743, M815, I880 50 EGF-like repeat and discoidin I-like domain-O43854 C59, C116, C154, M325, W351, A356, A366, W367, L378, V380, V388,I391, A396, V405, Y408, L410, A411, Y422, containing protein 3 A453,I456, I458, I467, L469, L473 51 Tolloid-like protein 1 (EC 3.4.24.—)O43897 A148, A149, W157, I162, F178, A181, W185, V191, I203, F205, I226,V238, V239, L242, V245, I246, F248, H250, H252, V261, I268, F276, I296,M297, H298, I313, A340 52 Peroxisome biogenesis factor 1 O43933 V19,V108, I155 53 Kalirin (EC 2.7.11.1) O60229 L2148 54 Cubilin (460 kDareceptor) O60494 Y952, I962, I970, L1020, F1024, I1037, Y1068, C1074,Y1076, I1086, L1095, L1107, I1109, F1143, F1154, A1156, C1191, W1193,L1195, A1202, F1203, M1255, F1270, A1272, V1281, L1291, C1306, W1308,V1318, V1368, L1370, F1382 55 Gremlin-1 O60565 C178 56 Toll-likereceptor 5 O60602 L72, L75, L94, L97, A114, L121, L124, L144, L147,I157, L169, I175, F177, I182, L190, L314, L317, L338, L341, L359, V362,I365, A425, V447, L450, L475, V497, L507, L531, L553, I555 57ATP-binding cassette sub-family C member 9 O60706 M702, I703, V704,C709, L714, L715, A717, I718 58 Voltage-dependent L-type calcium channelO60840 A252, A700, I707, A1015, V1082, A1095, Y1120, A1372, M1389subunit alpha-1F 59 Matrix metalloproteinase-20 O60882 L45, Y49, L75,L81, L122, I126, V138, A141, V142, A145, L146, A148, W149, V153, L155,A165, I167, I169, F171, A190, F193, F205, W211, L220, F221, V223, A224,A225, F228, A231, L232, L234, A242, L243, M244, Y245, Y250, L258, V263,I266, L269 60 Low-density lipoprotein receptor-related O75197 L35, L36,F37, A38, V43, L62, A65, A67, V68, V77, Y78, W79, V82, A86, I87, L113,L122, Y123, W124, I132, V134, protein 5 M165, Y166, W167, I176, A179,M181, V190, A212, I219, A242, L250, W252, I260, H261, I284, V286, L309,L311, L312, C321, C323, L344, L345, L346, A347, I355, L357, A375, Y388,W389, A396, I397, L430, Y431, W432, I440, V442, M473, Y474, W475, I484,A487, L489, L517, W519, I530, L545, I568, L588, M589, C605, L615, C616,F617, C627, I1274, C1323 61 Core histone macro-H2A.1 O75367 A19, F23,V25, M28, I32, H36, V43, A45, V47, Y48, M49, A50, A51, V52, L53, L56,I60, L61, A64, A67, A68, V76, H80, I81, L83, V85, L91, V98, A101, L197,L199, I200, I204, L207, A208, F210, A214, I215, I216, I223, L233, F241,V245, L255, A258, A270, V273, I274, H275, C276, L290, V294, C297, L298,A301, I309, A310, F311, I314, A326, A327, I330, L331, A333, I334, F338,I346, V349, F351, Y362, M366 62 Filamin-B O75369 F22, C26, L30, I37,L40, L44, L50, I51, L53, L54, V80, V82, A83, L84, F86, L87, I92, I102,I110, L111, L113, V114, L117, I118, I123, L145, W148, I149, I153, F161,W165, A170, L171, A173, L174, V175, A179, C183, A198, A201, M202, A205,L209, V211, V214, I215, I220, V230, M231, Y233, L234, F237, A257, A275,V279, A284, V291, V317, H327, V329, V331, F333, I338, V345, V1043,F1061, I1063, A1068, V1097, Y1099, Y1107, V1109, I1111, I1118, A1125,I1127, V1136, A1138, V1156, A1161, A1170, V1192, Y1194, Y1202, L1204,M1206, Y1208, V1220, I1231, V1243, F1251, V1253, I1270, Y1290, V1292,Y1294, H1302, V1304, V1306, V1320, V1331, A1341, F1349, V1351, A1356,A1385, Y1387, Y1395, V1397, I1399, I1406, V1413, V1424, V1435, V1445,A1450, V1459, V1481, V1493, V1495, Y1497, I1502, V1509, V1511, V1520,V1532, A1534, F1540, I1542, A1544, A1547, I1556, V1578, Y1580, Y1588,I1590, V1592, Y1594, I1599, I1606, A1608, A1614, C1617, F1636, V1638,A1643, V1648, V1652, I1674, A1678, Y1684, I1686, V1688, I1695, V1702,A1704, V1755, V1764, V1784, V1786, H1796, M1798, I1800, I1807, V1824,F1842, I1844, V1878, Y1880, Y1888, I1890, V1892, A1906, I1908, I1964,F1966, H1974, V1976, I1978, V1994, A2002, A2005, F2023, V2025, V2059,Y2061, Y2069, V2071, F2075, V2087, I2089, V2133, H2153, V2155, H2165,V2167, V2169, V2185, V2196, F2214, I2216, V2250, Y2252, A2254, Y2260,V2262, I2264, I2271, V2278, V2280, I2281, A2287, L2290, L2300, I2310,L2312, A2315, I2319, V2323, V2345, H2355, I2357, V2359, F2361, V2373,V2387, L2394, F2405, I2407, A2412, V2440, Y2442, Y2450, I2452, V2454,Y2456, I2462, A2469, A2512, V2515, A2525, V2535, C2537, V2571, V2575,V2585, W2587, I2592, V2599 63 Vacuolar protein sorting-associatedprotein O75436 F42, V48, V52, H65, I68, I70, F72, V73, I76, L101, F111,V114, V126, L128, Y130, F131, L132, V134, V151, M166, 26A L174, I176,F178, Y180, Y185, I191, I195, M207, L209, L211, A231, I246, I248, L250,L252, F268, V270, Y272, L274, L276, L278, I292 64 Low-densitylipoprotein receptor-related O75581 L23, L24, Y25, A26, L31, V34, V47,L50, A53, A55, V56, F58, V59, I65, Y66, W67, V70, A74, I75, V90, V91,L94, L100, protein 6 C102, L109, Y110, W111, I119, V121, L128, M152,Y153, W154, I163, A166, M168, I177, L189, L196, Y197, W198, A199, I206,A218, V219, L224, A229, L232, L237, Y238, W239, I247, L248, A249, C250,I271, A273, L296, C297, L298, M299, C308, C310, L317, L331, L332, L333,A334, L339, I342, L344, A362, Y375, W376, A383, I384, A414, L417, Y418,W419, I427, V429, L453, M460, Y461, W462, I471, A474, A475, L476, V485,A496, I504, W506, M517, I532, W547, I555, L575, M576, C592, L602, C603,L604, C614, L634, L635, F636, I642, I645, A664, A666, I676, Y677, I686,A689, V700, V712, L719, Y720, W721, A722, I729, V731, L755, M762, W764,I773, A776, A777, M778, V787, A793, I798, L805, W807, I815, A829, L832,I845, W847, I855, A858, I869, V876, V881, C893, L903, C904, A906, L936,L937, F938, I944, L959, V967, A969, L979, Y980, W981, I982, I989, A992,Y1027, I1028, Y1029, C1032, I1038, V1040, V1051, L1052, A1061, V1062,M1071, Y1072, F1073, I1083, A1086, A1087, L1088, L1116, F1117, W1118,A1119, I1126, L1157, W1159, I1160, I1167, L1188, C1207, I1217, C1218,L1219, C1313 65 Oral-facial-digital syndrome 1 protein O75665 M834,H851, V852, A854, A858 66 Protein XRP2 O75695 V57, F62, I64, C67, C70,I72, I74, F75, V81, I83, C86, C89, I91, F92, L93, V96, V100, F102, C105,C108, C110, L112, A113, C114, F117, V119, C122, L125, V127, L129, C131,I137, I143, F145, F148, W150, Y152, L155, F157, F159, A162, F167, W171,L189, V195, V199, L207, V221, C236, L237, V238, V239, A248, A250, L253,M257, V270, A277, V280, A285, V297, A299, L300, F302, A307, V308, C311,A333, F340, A344 67 Gap junction beta-3 protein O75712 L25, A39, W44,F51, C60, C64, W77, V84, I92, L135, L149, C164, V167, C176, M191, C19868 Isocitrate dehydrogenase [NADP] O75874 V10, V11, M13, M18, I21, I22,W23, L25, I26, L30, I31, V35, L39, L44, I46, A60, A61, A63, I64, V69,V71, C73, A74, I76, cytoplasmic I99, I102, V107, F108, I112, I113, C114,I117, W124, I128, I129, I130, H133, A134, A179, I189, F192, A193, F197,M199, A200, L207, L209, F223, I226, F227, F239, I244, M254, A258, F265,I266, W267, A268, C269, V281, A282, Y285, M290, M291, L295, V296, C297,V303, A305, A307, A308, I330, A331, I333, F334, A335, W336, L340, A344,L352, A353, F355, A356, A358, L359, V362, I367, F371, M372, L376, A377,A378, F397, M398, L401, L405 69 Tumor necrosis factor ligand superfamilyO75888 L219, L225 member 13 70 Dysferlin O75923 L2, V86 71 Multiple PDZdomain protein O75970 M129, A130, F138, L140, I165, V167, A176, I188,L189, A190, I191, L196, A205, V216, L218, V219, I220, A221, I258, L260,V279, A290, I302, L303, I305, L310, V318, V329, L331, I333, A334, V378,L380, I405, V407, A415, V416, I422, I428, V431, L436, A444, V455, L457,L459, L703, I728, I730, I738, A739, L745, L751, V754, L759, A767, A774,V779, I781, V783, V1152, L1154, L1162, I1185, I1187, A1196, L1202,I1208, V1209, V1211, L1216, A1219, A1224, V1235, F1237, V1239, I1337,L1353, A1365, V1375, F1376, I1377, A1386, L1398, L1399, I1401, L1406,A1414, A1421, V1425, I1427, I1428, F1429, I1430, A1435, I1630, I1632,I1654, I1656, A1664, A1665, I1677, V1680, L1685, A1693, V1704, L1706,L1708, I1726, L1728, V1749, A1760, I1772, V1788, V1799, V1803, I1890,I1892, A1901, I1916, A1929, I1940, M1942, V1944, I1988, L1990, L1997,I2014, V2016, A2025, I2037, V2040, L2045, A2053, L2057, V2064, L2066,V2068 72 Nebulette O76041 A961, F975, I981, V996, L1005 73 Bestrophin-1O76090 V90, V158, F248 74 Serine/threonine-protein kinase 10 O94804 A53,A62, A64, I82, I84, A86, C88, I93, V94, L106, I108, M109, V118, I121,M122, L125, L129, I134, V136, V137, C138, (EC 2.7.11.1) M141, L142,A144, L145, L148, H155, L158, A160, V163, L164, M165, L167, I171, L173,F176, V178, A180, A200, A218, I220, L223, L227, I228, M230, V245, L246,I249, F267, F270, A274, L275, A285, L288, F293, V294, L303, L306, V30775 Tumor necrosis factor ligand superfamily O95150 A97, L99, L117, M132,L139, I141, Y147, I149, V153, F155, A168, I177, V179, V180, I181, I212,L220, L226, V228, member 15 V230, V236, F245, F246, A248 76Interleukin-18 receptor accessory protein O95256 L165, I173, C175, W191,C221, A236, V238, C273, A275, F277, W289, V326, F335, C337, V339, V350,L352 77 Bile salt export pump (ATP- binding cassette O95342 A452, L453,V454, A464, L467, I468 sub-family B member 11) 78 Tumor necrosis factorreceptor superfamily O95407 C49, C52, C91, C132 member 6B 79Apolipoprotein M O95445 F49, I50, A51, A53, A54, I69, V70, L145, L146 80Gap junction beta-6 protein O95452 I25, A39, W44, F51, C60, C64, H73,W77, V84, A92, I140, F154, C169, I171, C180, M195, C202 81Follistatin-related protein 3 O95633 V37, W39, A70, V134, C135, C146,L148, L159, C195, C211 82 Interleukin-33 O95760 A124, L126, I134, V159,L160, L161, M183, V184, L186, L194, A196, V203, A216, F217, F218, V219,C227, F230, C232, I240, L247, A248, F265 83 EGF-containing fibulin-likeextracellular O95967 C71, C109, C162, C241, C281 matrix protein 2 84Cytochrome b5 P00167 I17, L28, I29, L30, V34, L41, L51, A55, L84 85L-lactate dehydrogenase A chain P00338 I23, V25, V26, V28, A34, C35,A36, I39, L40, M41, A45, L48, A49, L50, V51, L58, L91, V92, I93, I94,L109, V110, V114, F117, F119, I120, I121, V124, C131, L133, L134, I135,V136, V140, I142, L143, V146, A147, V158, I159, C163, F170, M174, C185,V189, L190, V198, V200, M204, V206, L218, V230, V234, V256, A257, L259,A260, I263, V273, I277, I283, V287, F288, L289, V291, C293, L295, L316,A320, L323 86 NADH-cytochrome b5 reductase 3 P00387 L45, L47, F60, F62,L71, L73, I79, L81, V106, L108, V109, I110, M127, L131, F142, L149,F157, V175, M177, I178, A179, I184, M187, L188, V190, I191, I194, C204,L206, L207, F208, I216, L217, L218, L222, F233, Y237, L239, I258, L270,V271, L272, M273, C284, L288 87 Cytochrome c oxidase subunit 2 P00403I83, I97, W106, Y108, V142, L144, I150, M152, I154, H161, W163, A164,V165, L168, A174, F184, M207, I209, V210, L211 88Phenylalanine-4-hydroxylase P00439 A34, I35, L37, F39, V51, F55, F79,F80, L83, L91, I94, L98, A104, L109, W120, I125, L128, F131, A132, A165,W187, V190, F191, L194, A202, C203, Y206, L213, F219, I224, L227, V230,F233, L234, F240, L255, L258, A259, F260, V262, F263, C265, Y268, I269,I283, C284, L287, L288, H290, V291, L293, F294, F299, A300, F302, I306,A309, L311, A313, I318, L321, A322, I324, F327, V329, L333, I340, A342,Y343, A345, L347, L348, L354, C357, A373, L385, Y386, Y387, A389, A395,V399, F402, A403, I406, F410, I421, L424, I432, A434 89 Superoxidedismutase P00441 A5, C7, L9, V15, I18, I19, F21, V30, V32, I36, L39,H44, F46, H47, V48, H49, A61, H64, H72, H81, V82, L85, V88, A90, [Cu—Zn](EC 1.15.1.1) A96, V98, V104, I105, L107, I113, I114, L118, V119, V120,H121, A141, A146, C147, I150 90 Coagulation factor VIII P00451 L26, A28,L90, L91, I95, I105, L107, V115, L117, A119, A131, V147, Y155, W157,Y177, L191, I192, A194, L196, V197, C198, L217, F218, A219, F221, H251,V253, Y256, V272, W274, V276, I277, I288, F295, I307, A315, L319, C329,M339, A341, V343, V345, I405, A406, A407, Y414, A415, L431, Y442, V445,F447, I467, L472, L480, I482, F484, Y492, I494, L517, Y530, W532, Y552,L566, I567, L570, L571, I572, C573, L594, F595, F598, Y605, M633, I636,V640, V648, W656, I658, V670, F677, L689, V697, M699, M701, L709, C711,M721, A723, L725, I1719, A1720, A1721, V1752, V1753, F1754, H1774,L1775, L1777, L1778, I1782, A1784, I1790, V1792, F1794, Y1802, F1804,V1826, W1836, V1838, M1842, C1851, A1853, Y1856, H1867, L1870, I1871,L1874, L1875, V1876, C1877, V1892, F1895, A1896, L1897, F1899, F1902,F1937, H1938, A1939, I1940, L1948, L1951, M1953, A1954, I1959, W1961,Y1962, L1963, L1964, H1973, I1975, F1977, F1982, L1997, V2005, V2017,C2019, M2029, F2033, V2035, M2046, A2066, A2070, A2080, W2081, I2099,I2100, H2101, A2108, I2117, F2120, I2122, Y2124, Y2134, F2145, I2163,I2164, A2165, L2181, L2185, M2186, C2188, C2193, M2199, I2209, A2220,W2222, A2227, A2237, W2238, L2249, V2251, F2253, V2259, V2262, V2267,M2274, V2276, F2279, I2281, F2302, L2316, L2325, I2327, I2336, A2337,L2338, M2340, V2342, A2347 91 Coagulation factor XIII A chain P00488L46, H65, Y70, L75, I76, V77, F83, V85, I87, F89, F100, V102, Y104,V105, I106, V120, A133, V136, V143, L145, I147, V155, F158, Y161, V162,A163, Y182, I183, L184, F185, V194, L196, Y205, V206, I213, F214, W226,I235, C239, V242, M243, L250, V259, M266, V275, L276, A292, W293, I299,Y303, V310, C315, W316, V317, F318, A319, V321, F322, L326, C328, L329,I331, A333, V336, Y339, A342, L349, I353, L355, Y373, H374, C375, W376,A379, M381, F390, A395, V396, C410, A413, A417, I418, H420, H422, A429,V432, F433, A434, V436, L440, I441, Y442, I461, I465, V466, Y482, L493,A498, V519, M521, F523, F534, L536, I538, F540, I550, A552, Y553, L554,A556, I558, Y561, V576, L578, I590, Y595, L605, H606, F607, F608, V609,A611, I613, V619, L620, L628, V642, M647, V649, V651, F653, L661, V664,V666, L668, I684, C696, L706, I707, A708, M710, L715, H717, V718, V72492 Hypoxanthine-guanine P00492 V35, I37, I42, L49, A50, V53, M57, I62,V63, A64, L65, C66, L68, F74, F75, L78, L79, I82, I93, I100, L125, V130,L131, phosphoribosyltransferase I132, V133, I137, M143, L146, L149,V150, V160, A161, L163, L164, F181, I183, V188, V189, Y191, A192, F199,L202, V205, C206, V207 93 Tyrosine-protein kinase P00519 L88, C100,A102, V111, W127, A137, L141, F149, L150, V151, I163, L165, A179, L198,V199, H202, L213, A217, I242, ABLI (EC 2.7.10.2) V268, V270, F283, L284,A287, V289, M290, I293, L298, L301, V304, C305, Y312, I313, I314, L323,L327, V335, V339, L340, M343, A344, I347, A350, M351, L354, I360, H361,L364, A365, A366, C369, V371, V377, V379, F382, L384, F401, A407, L411,V422, W423, F425, V427, L428, L429, Y440, V448, L452, M458, C464, M472,C475, W476, F486, I489, F493 94 Epidermal growth factor P00533 L41, F55,C58, V61, L65, I67, V70, L79, I82, V85, Y88, V89, L90, I91, A92, V96,I99, L101, L104, I106, I107, A118, receptor (EC 2.7.10.1) L119, A120,V121, L132, L135, M137, L140, I143, A147, V148, F150, L156, V159, I167,V168, C199, W200, C223, C236, A237, A238, C240, C260, V300, V301, C326,C337, I340, F345, I351, I356, F359, C362, I365, L369, I371, V374, A375,L392, L395, V398, I401, L405, L406, I407, L417, A419, F420, L423, I426,L438, A439, V440, V441, L443, I445, L448, L450, L453, I456, V461, I463,L469, C470, Y471, A472, I475, L480, C499, C510, C515, W516, C571, C62495 Adenylate kinase P00568 L5, I10, F12, V13, V14, C25, I28, I60, L73,L76, M80, F90, L91, I92, Y95, F105, I109, L114, L115, L116, V118, M125,isoenzyme 1 I146, V160, Y164, V173, V186 96 Prothrombin (EC 3.4.21.5)P00734 Y87, C90, A93, L100, C103, A109, Y116, C129, C157, W168, C169,Y170, C181, I183, A242, C262, V272, W273, C274, Y285, C286, V295, F324,F329, C336, L355, I364, V365, A370, M374, W377, V379, M380, L381, F382,L390, C391, A393, L395, I396, W400, V401, L402, A404, A405, H406, C407,L408, L409, L422, L423, V424, I426, L444, H450, I463, A464, L465, M466,L468, V472, I478, H479, V481, C482, L483, A489, L492, L493, A495, V501,W504, L507, L523, V525, V526, L528, I530, V531, C536, I544, M548, F549,C550, A551, A563, C564, F572, V573, M574, W582, M585, I587, V588, C594,Y600, F602, Y603, H605, V606, F607, L609, W612, I613, V616, I617 97Coagulation factor IX (EC P00740 C128, V132, V227, A233, V242, V243,L244, I256, V257, I262, V263, A265, A266, I275, V277, V278, A279, I316,3.4.21.22) A317, L318, L319, L321, V331, V353, W356, L369, V374, C382,F395, C396, A397, H415, V416, L425, I428, I443, Y444, V447, Y450, V451,I454 98 Coagulation factor X (EC P00742 C121, C136, I235, V236, C241,C246, A250, L251, L252, I253, C261, I265, L266, I271, L272, A274, A275,C277, 3.4.21.6) V286, V288, V302, I309, H311, I323, A324, V325, L326,L328, V338, A341, C342, A349, L353, G359, V361, F364, L377, M379, L380,V382, C390, L392, M402, C404, A405, H423, V424, F432, V433, I436, A444,I451, Y452, V455, F458, W461, I462 99 Complement factor D (EC P00746I26, L27, M40, A41, V43, C51, V54, L55, V61, L62, A64, C67, V78, L80,L115, L116, L117, L118, L120, L126, L133, 3.4.21.46) C148, V150, A151,W153, V169, L171, C179, I189, L193, C195, A196, C204, L212, L218, V221,V222, C229, Y238, V241, I248 100 Plasminogen (EC 3.4.21.7) P00747 A31,C49, C53, C61, A63, F64, C73, M76, Y111, W127, C152, W163, C164, Y165,C176, I178, M186, Y193, W209, [Cleaved into: Plasmin H217, Y219, C234,W244, C245, F246, C257, I259, Y283, C296, W299, L319, C324, W334, C335,H336, C347, I349, heavy chain A; Activation Y385, C398, W401, H407,H409, L421, C426, W436, C437, F438, C449, L451, Y489, C502, W505, H513,C531, W542, peptide; Angiostatin; C543, Y544, C555, V557, C577, V581,W594, V596, L598, C607, L611, V617, L618, A620, C623, Y633, V635, I636,Plasmin heavy chain A, L637, V654, I666, A667, L668, L669, L671, V681,I682, A684, C685, C699, I701, W704, L716, A719, L721, V723, short form;Plasmin light C729, L735, L744, C745, A746, H748, L764, V765, C766,Y772, L774, V777, A785, V792, Y793, V794, V796, F799, chain B] V800,I803 101 Coagulation factor XII (EC P00748 C135, V158, C161, C163, C209,A388, A389, A398, L401, L408, A410, A411, L414, V425, L427, L462, A463,L464, 3.4.21.38) L465, L467, V482, C500, A503, W505, C532, C548, A549,L567, V568, C569, L580, I583, V598, V602, I609 102 Complement factor B(EC P00751 L58, A96, C103, Y121, I127, C145, C158, C165, V177, V187,C205, M223, V230, A231, F234, L235, I242, M269, I271, 3.4.21.47) Y272,L273, V274, L275, I281, F286, A289, C292, L293, I297, V300, Y309, L311,V312, Y314, A315, V322, V324, V335, L339, I342, A358, L359, V362, V383,I384, I385, L386, M387, L391, V401, I405, L409, I411, Y426, V427, F428,V430, I439, A443, H451, F453, V455, M458, L461, V464, F465, M468, V481,W495, A497, I499, V501, C511, M512, A514, V515, V516, F520, V521, L522,A524, A525, C527, F528, V530, V539, V541, I569, V577, A578, L579, I580,L582, C596, C599, A606, L607, L622, I628, A630, L631, F632, V633, V645,I647, C656, A660, A663, V669, V675, V676, F680, L681, C682, C695, L703,I704, V705, F711, I712, V714, V716, V721, A738, F741, H742, I743, L745,V748, L752, L756, L761, L764 103 Renin (EC 3.4.23.15) P00797 I90, I92,F99, V101, V102, F103, V110, W111, V112, C117, A123, C124, F130, V154,I162, I163, V165, V170, M173, F174, M180, V193, V194, M196, F198, I209,F210, I213, V218, V223, F224, F226, Y227, Y228, I242, I262, V266, W267,I269, M271, V274, L288, A289, V291, I298, I305, L308, M309, V322, V323,C325, L331, I334, F336, L338, Y343, L345, Y350, F352, C362, L364, A365,I366, A380, L381, A383, F385, I386, Y390, F393, I400, F402, A403 104Carbonic anhydrase 2 (EC P00918 W16, V31, I33, Y51, I59, A65, F66, V68,F70, A77, V78, L79, Y88, L90, F93, H94, F95, H96, W97, H107, A115, A116,4.2.1.1) L118, H119, L120, V121, H122, W123, A133, V134, L140, A141,V142, L143, I145, F146, L147, V149, L156, V159, V160, V162, L163, I166,F175, F178, L183, L184, L188, Y190, W191, Y193, L197, L202, L203, C205,V206, W208, I209, V210, L211, I215, V217, V222, F225, L228, F230, M240,L250, I255, A257 105 Argininosuccinate synthase P00966 V7, V8, L9, C19,I20, L21, W23, L24, V31, I32, A33, Y34, L35, A51, V64, F68, V69, F72,I73, I77, L89, L93, A94, C97, (EC 6.3.4.5) A99, I105, A106, Y113, C132,A143, F150, Y163, A164, L185, M186, H187, Y190, L195, L206, L223, I225,F227, V235, V238, L250, F251, L254, V257, A258, H261, V263, V269, I281,A286, I289, L290, A293, H294, I297, F317, A318, V321, Y322, C331, I338,V345, V349, V351, V353 106 Serine protease inhibitor P00995 V46, C47,L60, C61, I71, I73 Kazal-type 1 107 Antithrombin-III P01008 M49, A75,V80, L83, A86, F90, A91, F94, Y95, L98, I108, F109, L110, L113, I115,A118, F119, A120, M121, A126, C127, L131, L134, M135, V137, F138, F140,I143, I151, H152, F153, F154, F155, A156, L158, L162, A166, A175, L178,F179, V197, A200, F207, I218, V222, I230, I234, A238, L242, V244, L245,V246, L247, V248, I251, F253, W257, F261, F271, A281, M283, M284, V301,L302, L304, F306, I311, M313, V314, L315, I316, L317, V327, L331, L343,L348, V349, V350, M352, I357, L363, L367, L372, L375, L383, I386, A388,L394, V396, A399, H401, A403, L405, V407, A414, A415, A416, A419, V420,V421, I422, A423, F434, A436, F440, L441, V442, F443, I444, V447, I453,F454, M455, V458, A459 108 Alpha-1-antitrypsin P01009 F47, I50, L54,F57, A58, F59, L61, Y62, L65, I74, F75, F76, V79, I81, A82, A84, F85,A86, M87, L88, I100, L101, L104, F106, I111, I116, F120, L123, L124,L127, L134, L142, F143, L144, F154, V158, L161, Y162, V169, F171, A177,I181, V185, I193, V197, V205, F206, A207, L208, V209, I212, F213, F214,W218, F222, V224, F232, V234, V242, M244, M245, F251, I253, L259, V263,L264, M266, Y268, A272, A274, I275, F276, F277, L278, L284, L287, L291,I295, F299, L300, A308, L310, H311, L312, I317, L323, L327, L330, I332,V335, A340, L342, V345, L351, L353, A356, V357, H358, A360, V361, L362,I364, A371, A372, A374, M375, F376, L377, A379, I380, V388, F390, F394,V395, F396, L397, M398, L407, F408, M409, V412, V413 109 AngiotensinogenP01019 V44, A103, V106, L109, A110, L113, F115, I117, Y118, V133, L134,A138, V139, F140, L143, A144, L146, L158, L16 2, V164, L175, V180, L181,A183, L184, A186, V187, L191, V192, L203, L205, V208, V209, V211, F212,L217, L219, F223, L227, Y230, F241, A247, M255, V258, L276, A277, F278,Y281, V282, F284, M288, F291, F300, V310, L313, V331, V334, A340, C341,L342, L343, L344, I345, V356, F361, I377, L379, M381, L384, L392, L395,L396, I404, L405, L409, L411, L414, V424, I428, F430, L432, L456, F460,L461, A463, V464, A469, A471, L472, H473, F474, L475, V478 110Complement C3 P01024 M25, I28, I29, L34, M42, L44, A46, H47, V55, V57,V59, L76, V86, F88, I90, V106, V108, A110, F112, V117, V121, L122, V123,Y129, I138, Y139, V145, Y147, I149, F150, V152, V163, V165, I167, V188,L189, W204, I206, A208, Y210, F222, V224, F232, Y243, I245, L251, V253,I255, A257, V265, A269, V271, F273, I275, L284, I293, V300, L302, L319,L324, V326, A328, V330, I346, I348, I355, F364, M368, F370, L372, V374,V376, A384, V387, V389, L400, A407, L409, I422, V424, A443, Y446, Y455,L456, L465, V473, F475, I487, Y490, L493, I494, I521, I526, F529, L531,V532, A533, Y534, Y535, L537, V546, V547, A548, V555, I585, A591, V593,V596, A597, V602, I616, W617, V620, V638, F639, A642, L644, F646, C693,C694, M698, M703, V723, F724, C727, C728, I731, W802, A806, V825, F829,L833, V839, V840, V845, I847, A849, L851, L860, V862, V864, L866, A871,C873, A876, I888, V896, Y898, V899, I900, V901, V910, V912, A914, A915,V916, V925, L929, V931, L947, I962, V971, I980, L982, V987, M990, A994,V995, A997, L1000, L1003, C1010, M1015, I1016, M1018, V1022, I1023,A1024, V1025, Y1027, L1028, A1045, I1049, L1057, A1058, F1059, A1065,F1066, A1067, A1068, F1069, A1073, L1078, A1080, Y1081, V1082, V1083,V1085, F1086, L1088, A1089, V1090, L1100, C1101, A1103, V1104, L1107,V1117, F1118, V1124, H1126, M1129, M1141, A1142, A1145, F1146, V1147,L1148, I1149, L1151, A1154, C1158, V1162, L1165, A1172, L1176, Y1180,L1183, Y1187, V1189, A1190, I1191, A1192, A1195, L1196, A1197, L1202,F1210, W1220, L1227, Y1228, V1230, A1232, Y1235, A1236, L1237, L1238,A1239, L1240, L1241, V1249, V1252, V1253, L1256, Y1266, A1271, F1273,M1274, V1275, F1276, A1278, L1279, A1280, Y1282, L1292, L1294, V1296,L1298, I1311, F1330, V1332, A1334, L1342, V1344, Y1348, A1350, F1361,L1386, I1388, C1389, I1402, L1403, I1405, M1407, M1408, F1411, A1412,L1418, L1421, I1429, L1444, I1446, Y1447, V1451, A1460, F1461, V1463,L1471, A1476, V1477, V1479, A1481, Y1482, Y1483, C1489, Y1493, C1518,A1536, Y1543, V1544, Y1545, L1549, F1558, Y1561, M1563, I1565, F1584,C1590, Y1602, L1603, M1604, W1605, Y1620, L1649, F1652 111 Complement C5P01031 V24, I25, A27, F31, V33, A35, I39, V40, I41, F50, A52, I54, I56,V71, L73, L85, I87, V102, V106, M117, L126, Y135, V141, V143, V145,Y146, L148, L161, F163, I183, I190, W199, I201, A203, Y205, F217, V219,I238, F246, I248, I250, A252, V260, A263, V265, I267, F269, I271, M283,L292, F301, V307, L310, L323, I325, V327, V329, Y347, L363, I371, V373,V375, V388, L390, A418, V428, L431, F433, V435, A448, A454, Y457, L465,I484, V486, Y499, L502, I503, I526, M534, L540, L541, V542, Y543, Y544,L554, V555, L561, I563, V573, V588, L590, M592, V600, A601, L602, A603,A604, V605, A608, V609, L620, A643, V645, F646, A649, L651, F653, I683,A687, V695, C698, C699, C711, C724, I725, A727, F728, C731, C732, V734,A735, V780, W797, I799, V802, I804, C810, V819, V823, V833, I839, L841,V845, Y846, C856, V888, V896, V900, L901, I910, F912, L914, L927, L944,V968, L977, V979, V984, I987, L988, A1008, A1010, L1012, V1015, F1019,Y1020, V1021, Y1024, L1025, L1049, V1068, W1077, L1078, A1080, F1081,A1082, L1083, V1089, L1104, L1107, I1127, L1142, Y1143, A1146, F1147,V1149, I1150, I1152, A1155, C1159, I1164, A1167, L1168, A1171, L1175,F1186, L1188, A1189, I1190, A1192, Y1193, A1194, F1205, I1208, F1227,W1228, A1245, V1248, A1252, Y1253, A1254, L1255, L1256, L1259, V1267,V1270, I1271, W1273, L1274, F1284, I1291, A1293, I1294, L1297, L1303,L1309, M1311, I1313, V1315, M1328, F1333, V1340, L1346, V1348, A1357,V1359, V1361, V1365, I1402, A1404, A1406, Y1408, H1421, A1422, V1423,M1424, I1426, L1439, L1442, F1450, V1460, L1462, I1467, V1475, F1477,I1479, A1491, F1493, V1495, Y1498, H1499, C1505, V1519, A1545, A1552,I1557, Y1559, A1560, Y1561, V1563, Y1577, A1579, L1581, A1590, I1598,F1600, A1609, Y1617, L1618, I1619, M1620, A1624, Y1637, I1645, C1657,F1660, L1664, F1667 112 Complement C5a P01032 C22, C47, A50, C55anaphylatoxin 113 Cystatin-C P01034 V49, A52, A56, L90, V92, L94, G95,C109, C123, F125, I127 114 GTPase NRas P01111 Y4, L6, V7, V8, V9, A11,V14, L19, L23, V29, V44, I46, C51, L52, L53, I55, L56, A59, M67, M72,F78, L79, C80, V81, F82, A83, I84, F90, I93, L95, Y96, I100, V103, V109,M111, V112, L113, V114, L120, V125, A130, A134, A146, V152, A155, F156,L159, V160, I163, M168 115 Platelet-derived growth P01127 V127, V153,V170, L172 factor subunit B 116 Low-density lipoprotein P01130 I40, V45,C52, I83, C95, C116, I122, C134, C155, I161, A166, C173, C204, C222,C318, C338, C352, C377, Y400, L401, receptor F402, F403, V409, M412,L414, I423, A431, L432, V436, I441, W443, I451, A480, V481, I488, Y489,W490, V498, V500, A501, M531, Y532, W533, I542, L547, V556, L575, W577,V578, I585, L605, L611, A612, V618, F619, W620, A627, I628, A631, A643,L646, C667, C677, C681, L682, C698 117 Transforming growth factor P01137L258, C293, C294, V295, F302, C326, L340, A341, L364, I366, C387, C389beta-1 118 Beta-nerve growth factor P01138 C136, V157, V159, V163, C189,A210, A218, A219, I223, I225 119 Vasopressin-neurophysin 2- P01185 C44,C52, I57, C58, C59, C65, A72, C75, C92, C98, A99, A100, C104, C105, C110copeptin 120 Somatotropin P01241 F36, A39, A43, L46, L49, A50, Y54, F70,C79, I84, L99, L101, L102, I104, L106, L107, L108, I109, W112, V116,L119, F123, A131, V136, L140, L143, I147, L150, Y186, L189, F192, M196,V199, F202, L203, V206 121 Insulin [Cleaved into: P01308 L35, A38, L39,I91, C95, L105, C109 Insulin B chain; Insulin A chain] 122 Insulin-likegrowth factor II P01344 L37, L41, F52, I66, C70, C75, L80, Y83, C84, A85123 Lymphotoxin-alpha P01374 A65, L67, I68, L94, L99, V101, Y107, V109,V113, F115, L131, H133, V135, L181, V198, F200, A202 124 Tumor necrosisfactor P01375 A90, V92, A94, A98, L105, V117, L124, V125, V126, L131,Y132, L133, I134, V138, F140, C145, V150, L152, H154, I156, A160, L202,L208, A210, V226, F228, I230 125 Interferon gamma P01579 Y6, I7, F10,C13, I14, A31, L34, A40, F52, L56, I67, M68, I72, V73, Y76, F77, L79,F80, I89, V93, I96, M100, F104, F105, F115, A132, I133, L136, M140, L158126 Interleukin-1 alpha P01583 I135, L136, A163, F166, A170, Y171, A178,V182, I183, Y192, I214, L221, F223, F234, I244, A245, V252, L254, F264127 Interleukin-1 beta P01584 C124, L126, L134, V135, L142, A144, V156,F158, M160, V163, V174, A175, L176, L178, L185, C187, M211, F215, V216,F217, L226, F228, I238, F262 128 Erythropoietin P01588 L39, A46, A49,C56, C60, L62, V68, A87, V90, L94, L97, A100, L118, V122, A125, L129,L132, L136, A141, A145, A162, L168, F169, F175, L176, L180, Y183 129Interleukin-2 receptor P01589 A38, L47, C67, C80, C125, V143, V148,Y150, C168 subunit alpha 130 T-cell surface glycoprotein P01730 L39,C41, A43, F51, W53, I61, L62, L69, L76, A80, W87, F92, L94, I95, I96,L99, Y107, C109, V111, V118, L120, L121, CD4 V122, F123, L134, L139,L141, L143, V153, C155, L169, V171, L174, W182, C184, V186, I199, V201,V219, F221, F223, L238, F254, V261, M274, L282, L284, A287, A292, L297,L299, L308, V312, L314, V315, V316, M317, L326, C328, V330, L340, L342,V358, W368, C370, L372 131 Ig epsilon chain C region P01854 I131, L133,C135, V137, W149, L178, W185, Y191, C193, V195, I237, C239, V241, V251,V280, L284, Y297, C299, V301, L310, V326, L343, C345, I347, F350, I355,V357, W359, V386, L390, V392, F403, C405, A407, V408, H409, A412, V418,V424 132 HLA class I P01889 M29, Y31, Y33, F46, V52, F57, V58, F60, A73,W75, I76, Y83, Y91, A95, L102, L105, L119, M122, C125, V127, Y140,histocompatibility antigen, Y142, Y147, I148, L150, L154, W157, A163,A164, A177, L184, C188, V189, L192, Y195, L196, L203, V213, A223, B-7alpha chain L225, C227, A229, F232, Y233, L239, W241, A269, A270, V271,V272, V273, Y281, C283, V285, H287 133 HLA class II P01903 F47, M48,F49, F57, V59, A77, A81, A84, A86, I88, L130, I131, C132, I134, F137,W146, F173, L176, L179, Y186, histocompatibility antigen, C188, V190,H192 DR alpha chain 134 HLA class II P01906 H50, F58, V60, I78, A85,M89, L131, I132, C133, V135, I138, W147, I174, L177, L180, Y187, C189,V191, H193 histocompatibility antigen, DQ alpha 2 chain 135 HLA class IIP01909 H50, F58, V60, A84, I88, L130, C132, V134, I137, W146, I173,L176, L179, Y186, C188, V190, H192 histocompatibility antigen, DQ alpha1 chain 136 HLA class II P01911 F36, L37, F46, F47, V53, F55, L56, Y59,V67, F69, F76, W90, L97, A103, C108, V120, V128, L138, L143, L144, V145,histocompatibility antigen, C146, V148, F151, W160, M171, L190, V199,Y200, C202, V204 DRB1-15 beta chain 137 HLA class II P01912 F36, L37,F46, F47, V53, Y55, L56, Y59, V67, F69, F76, W90, L97, C108, V120, V128,L138, L143, L144, V145, C146, histocompatibility antigen, V148, F151,W160, V171, L190, V199, Y200, C202, V204 DRB1-3 chain 138 HLA class IIP01920 F39, V40, F49, V56, Y58, V59, Y62, A70, F72, Y79, W93, L100,C111, L123, V131, L141, L146, L147, V148, C149, histocompatibilityantigen, V151, F154, W163, V174, L193, V202, Y203, C205, V207 DQ beta 1chain 139 Collagen alpha-1(I) chain P02452 C63 (Alpha-1 type I collagen)140 Collagen alpha-1(II) chain P02458 C57 (Alpha-1 type II collagen)[Cleaved into: Collagen alpha-1(II) chain; Chondrocalcin] 141 Collagenalpha-1 (III) chain P02461 C55, C1262, L1265, V1279, I1290, C1294,I1303, V1310, V1326, F1328, A1364, I1368, Y1370, A1377, L1390, L1392,F1400, C1417, F1429, Y1431, L1439, I1441, I1444, A1445, V1458, V1463,F1465 142 Collagen alpha-1 (IV) chain P02462 V1448, L1474, Y1475, L1487,Y1521, W1522, L1523, I1545, C1548, A1549, V1550, C1551, A1553, F1583,H1586, [Cleaved into: Arresten] C1604, F1613, I1614, C1616, C1622,C1662, V1664, C1665, M1666 143 Alpha-crystallin A chain P02489 L75, V77,V94, I96, V124, L129, L139, F141 144 Apolipoprotein A-I P02647 V35, L38,A39, Y42, L46, Y53, F57, L106, V117, L138, Y139, L198 145 ApolipoproteinE P02649 W44, A47, F51, L55, V58, V65, L69, L70, V74, L78, M86, L89,L96, L100, A109, L111, L115, A117, A118, L122, M126, V129, C130, L133,Y136, L144, L151, V153, L155, A156, L159, L162, L166, L173, L177, Y180,A194, L247, L270, V298 146 Fibrinogen alpha chain P02671 I675, Y692,W708, L714, L724, V726, L728, A738, Y740, V744, Y751, L753, A762, A765,H780, F785, C799, A800, [Cleaved into: W807, Y809, A815, L817, V841,W843, L853, V856, M858 Fibrinopeptide A; Fibrinogen alpha chain] 147Fibrinogen beta chain P02675 C241, I244, M254, Y255, I257, V268, C270,W279, I282, F292, Y299, C316, Y322, W323, I329, L340, L341, I342,[Cleaved into: M344, A354, H355, Y356, F359, V361, Y368, V372, A379,A382, L383, A387, H400, F405, C424, W432, W433, Y434, Fibrinopeptide B;A439, A440, Y447, Y452, V465, V466, W467, M477, M480, M482 Fibrinogenbeta chain] 148 Fibrinogen gamma chain P02679 C179, I182, Y193, I195,V206, C208, V219, F220, Y237, W253, I259, I262, Y270, A271, L272, V274,L276, A286, Y288, A289, F291, V293, Y300, L302, F307, A312, A315, F316,F321, H333, F338, F348, C352, A353, W360, W361, M362, H366, A367, H369,L370, Y375, Y380, Y389, I393, I394, W395, M405, M410, I412, I413, L418,H427, A431 149 Acetylcholine receptor P02708 V153, L154, A167, V177,V201, I203 subunit alpha 150 Band 3 anion transport P02730 M435, C479protein 151 Protein AMBP [Cleaved P02760 C287, A304, C333 into:Alpha-1-microglobulin 152 Transthyretin P02766 L32, V34, V36, A45, V48,V50, V52, L75, L78, F84, I88, Y89, V91, I93, Y98, W99, A111, A117, I127,A128, A129, L130, L131 153 Serum albumin P02768 V31, A32, F43, A45, L46,V47, L48, I49, A50, F51, A52, Y54, L55, C58, H63, L66, V70, A74, C77,C86, L93, L98, A102, M111, C114, F126, C148, F151, L163, A167, F173,A175, L178, F181, A182, A188, F189, C192, L202, L209, A215, C224, A225,F235, A239, A241, F247, A250, A253, V255, L258, V259, V265, C270, L274,L275, C277, A285, I295, L299, C302, V317, F333, V334, V339, Y343, F354,A359, V367, L369, L370, L371, L373, Y377, L381, C384, Y394, V397, F401,V405, C416, F427, L431, L432, V439, V442, L447, V448, V450, L454, V457,C461, A473, V480, L481, L484, V486, H488, V497, C500, F512, F531, A535,I537, A552, L553, V554, L556, V557, A563, L568, V571, F575, F578, V579,C582, F592, L607, L609 154 Ferritin light chain P02792 V13, A15, V17,L20, V21, Y24, A27, Y31, L34, Y37, F38, V48, F51, F52, L55, A56, Y63,L66, L67, M69, W90, A96, M97, A99, A100, M101, L107, L111, L112, L114,L126, L130, F134, M145, L149, L152, F167 155 Capsid protein/genotype DP03147 F9, L15, L19, F23, F24, A36, Y38, A54, L55, C61, W71, W102, F103,L108, F110, V120, F122, W125, A131, Y132, subtype adw (isolate UnitedA137, I139, L140 Kingdom/adyw/1979) (HBV-D) 156 Estrogen receptor P03372C185, V187, C188, V199, C202, C205, F209, C227, I229, C237, A239, C240,L242, C245, M250, A307, M315, L319, A322, M342, L345, L349, L354, M357,I358, W360, A361, V364, F367, V376, L378, L379, A382, W383, I389, L391,V392, L402, A405, L408, L410, V418, F425, F435, F445, V446, C447, L448,I452, L453, L454, V458, H474, I475, V478, I482, L486, M490, L507, I510,I514, M517, M522, M528, L540, L544 157 Fusion glycoprotein F0/strain A2P03420 F32, C37, A39, V40, A47, L48, V56, I57, I59, V76, I79, L83, A89,V90, L93, L158, V164, L171, V187, L188, L195, I199, L203, C212, I214,V220, F223, L230, I233, F237, V247, M251, L252, L257, L260, I261, M264,I266, M274, I280, V281, I288, S290, I291, L297, A298, Y299, V300, V301,L303, Y306, C313, C322, I332, C333, L334, Y342, C343, V349, F351, F352,V365, F366, C367, I379, L381, C382, C393, I395, I407, L410, A412, I413,V414, C416, C422, A424, V442, M447, V450, V459, I475, Y478, A490, V495158 Hemagglutinin [Cleaved P03441 A11, L13, C14, L15, A19, V26, V36,L42, V43, I51, C52, I58, C64, L66, I67, L70, L71, C76, F79, L86, F87,V88, F94, C97, into: Hemagglutinin HA1 Y98, Y100, Y105, A106, L108,V112, A113, L118, F125, A138, C139, F147, F148, L151, L154, L164, Y178,W180, V182, chain; Hemagglutinin HA2 H183, H184, Y195, V202, V204, I230,I232, Y233, I236, V237, I242, L243, I245, L251, I252, A253, F258, I274,C281, chain]/strain I282, I288, V309, L316, A317, A334, W343, Y351,A373, A425, L447, L455, C466, F467, I469, H471, C473, C477,A/Bangkok/1/1979 H3N2 I478, I481, A495 159 Hemagglutinin [Cleaved P03446I20, C21, I22, V33, V43, L58, C59, L69, C72, L74, I78, L79, Y95, I96,V97, L118, F122, C150, M163, L166, I188, V189, into: Hemagglutinin HA1F190, W192, I194, Y207, V216, M242, Y244, L249, V255, I257, L263, I264,A265, C294, L327, A347, Y364, A386, L460, chain; Hemagglutinin HA2 L468,H484, C486, C490 chain]/strain A/Duck/Alberta/60/1976 H12N5 160Hemagglutinin [Cleaved P03448 A8, I19, I21, V42, L48, L49, F57, C58,L66, L68, C71, I73, W76, I77, L78, C83, L86, W92, Y94, I95, V96, Y107,L117, into: Hemagglutinin HA1 L120, I121, V127, F133, C151, Y153, L163,L164, W165, I166, I177, I189, L190, Y191, F192, W193, V195, H196, H197,chain; Hemagglutinin HA2 Y208, V215, M217, I243, Y245, I249, L250, L256,V258, L264, I265, A266, Y269, A270, F271, F273, A281, C292, C296,chain]/strain V302, L303, I317, V324, L329, L331, A332, A349, M361,Y366, A388, V389, A440, L452, V459, L462, V466, L470,A/Shearwater/Australia/1972 C481, H486, C488, C492, M493 H6N5 161Hemagglutinin [Cleaved P03456 I19, C20, I21, V32, V42, Y57, C58, L68,C71, I73, I77, Y78, Y94, I95, V96, L117, F121, C149, I162, L165, I188,I189, into: Hemagglutinin HA1 F190, L191, W192, I194, Y207, V216, M242,Y244, L249, L255, I257, L263, I264, A265, C295, A348, Y365, A387, L461,chain; Hemagglutinin HA2 L469, H485, C487, C491, A509 chain]/strainA/Turkey/Ontario/6118/1968 H8N4 162 Hemagglutinin [Cleaved P03457 L10,I21, C22, I23, V34, V44, L51, L59, C60, L68, L70, C73, I75, I79, Y80,Y96, I97, V98, L119, F123, C151, M159, L162, into: Hemagglutinin HA1A174, I184, L185, F186, M187, W188, I190, Y203, V212, I238, Y240, L245,L251, I253, L259, I260, A261, C290, chain; Hemagglutinin HA2 H304, L323,A343, Y360, A382, L456, L464, H480, C482, C486 chain]/strainA/Turkey/Wisconsin/1/1966 H9N2 163 Neuraminidase (EC P03471 W87, I94,F97, I106, I114, V116, Y121, V122, C124, F132, A133, L134, L140, L158,L159, C175, A177, C183, L190, 3.2.1.18)/strain V192, C193, V194, A201,A203, F205, Y207, L223, C230, V231, C232, V239, V240, M241, I254, L255,F256, I257, A/Memphis/1/1971 H3N2 V275, C278, C280, Y281, Y284, V287,C289, I290, C291, V302, V303, I305, Y316, V317, C318, L321, V322, V349,W352, A353, F354, V360, W361, M362, Y374, F377, V379, I397, V398, I409,F410, I418, C421, F422, Y423, V424, L426, V436, W438, I443, V444, V445,F446, I464 164 Neuraminidase (EC P03472 L88, I95, A106, V107, V115,V117, Y122, V123, C125, F132, Y133, A134, L135, L159, I160, W162, C177,I178, C185, 3.2.1.18)/strain M192, I194, C195, I196, A203, A205, V206,I207, Y209, A221, L225, C232, V233, C234, C239, V241, V242, F243, I256,A/Tern/Australia/G70C/1975 Y257, Y258, F259, H276, I277, C280, C282,Y283, I289, C291, C293, V304, I305, I307, Y318, I319, C320, V323, L324,H11N9 V350, F353, Y355, W362, L363, I369, Y375, M377, L378, V380, A383,I397, V398, F410, M411, Y420, A422, C423, F424, Y425, V426, L428, V438,I445, V446, M448, C449, A464 165 Neuraminidase (EC P03474 F92, I114,I115, F119, V120, A121, F130, L132, L156, V159, A175, A176, A181, C182,I191, V193, A200, L201, V202, 3.2.1.18)/strain B/Lee/1940 I204, I221,L222, I232, C236, Y237, L238, M239, I240, A245, F253, L254, I256, I265,H273, C277, I287, C289, A290, C291, A298, F302, V303, L305, I314, L323,I333, H354, W364, M377, L379, M400, V401, F411, C424, I425, I427, M429,V430, H431, H439, A441, A442, A444, I445, Y446, L448, L454, L455 166Neuraminidase (EC P03476 F94, I106, V116, Y121, V122, C124, F132, A133,L134, L158, F161, C176, C184, M191, V193, C194, M195, A202, A204,3.2.1.18)/strain I206, Y208, L224, C231, C233, V240, A241, V242, V255,Y256, W257, I258, L277, C280, C282, I286, V288, C290,A/Turkey/Oregon/1971 I291, C292, W303, M304, I306, Y316, V317, C318,H322, V348, F351, F353, W360, L361, F373, I375, V378, L396, H7N3 V397,F409, I410, F417, F421, Y422, V423, L425, V436, I443, V444, F446, I464167 Neuraminidase (EC P03477 I105, V113, V115, F120, I121, F131, F132,L133, L157, C160, A177, W178, A180, A182, C183, L190, L192, I194, A201,3.2.1.18)/strain V202, A203, L205, M223, V231, C232, Y238, L240, I241,A250, Y252, I254, I257, I262, H274, F275, C278, C280, Y281,A/Turkey/Ontario/6118/1968 V287, C289, V290, C291, I303, F305, I313,C317, I320, F321, F350, F352, Y354, V358, W359, I360, F372, M374, H8N4V375, V382, I394, I395, F407, C422, F423, W424, V425, M427, W438, I444,F446 168 Neuraminidase (EC P03478 I98, I106, V108, F113, V114, F124,F125, L126, L150, V153, W171, A173, A175, C176, M183, I185, V187, A194,Y195, 3.2.1.18)/strain A196, I198, L216, V224, C225, I226, Y231, V233,M234, A243, Y245, I247, V255, H267, I268, C271, C273, Y274,A/Shearwater/Australia/1972 M277, V280, C282, V283, C284, L296, F298,C310, I313, F346, F348, V354, W355, A356, I360, F368, V370, L371, I378,H6N5 I384, V390, L391, F403, I415, C418, F419, W420, L421, M423, W435,F443 169 NADH-ubiquinone P03886 Y43, A50, A52, M53, F56 oxidoreductasechain 1 (EC 1.6.5.3) 170 Angiogenin (EC 3.1.27.—) P03950 F33, C50, I53,M54, C63, I66, F69, I70, H71, I77, A79, I80, L93, V102, C105, C116,Y118, V127, V128, V129, P136, L139 171 Coagulation factor XI P03951 F30,C46, C50, C56, L57, L58, F59, C76, L78, M120, A130, C136, C140, F148,F149, C165, L167, A220, V225, C226, C230, C236, F238, F239, C255, L257,A274, C283, V289, F301, C317, C321, C327, F329, F330, A337, C346, I366,I388, W401, V403, L405, C416, I420, I421, I426, L427, A429, A430, V444,Y445, V463, I481, A482, L483, L484, L486, V490, C500, C514, V516, W519,A535, I537, C545, Y549, I554, C560, A561, A570, L579, C581, V586, H588,L589, V590, I592, V607, Y608, V611, V612, Y614, I618 172 Catalase (EC1.11.1.6) P04040 A76, A79, A81, F85, V87, I91, A97, V99, F100, I109,A110, V111, F113, A117, F132, V134, F136, W143, L145, I152, F153, F154,I155, I159, F164, W183, W186, L193, V196, F200, I205, H209, M212, L222,V230, C232, F234, Y236, A250, L265, F266, A268, W277, F279, I281, M284,A289, F294, L299, V313, L316, V317, L318, V329, I332, A333, I343, L351,L355, V375, V443, Y447, L459, C460, I463, A464, L467, A478, V479, F482,V485, Y489, I493, L496, L497 173 RAF proto-oncogene P04049 I58, V60,L62, V72, L78, C81, L82, L86, A97, V98, A118, L126, V128, C152, C165,C176, V180, C184, V372, I405, V420, serine/threonine-protein I446, A449,A453, M456, L459, H466, M469, L476, V482, I484, F487, A513, V516, V531,Y534, V537, L538, M542, kinase (EC 2.7.11.1) M581, V585, C588, F599,I606 174 Glucosylceramidase (EC P04062 V54, C55, C57, F76, L108, F120,A123, M124, A127, A128, A129, I132, A139, L142, L143, L144, Y147, F148,I153, 3.2.1.45) Y155, I157, I158, V160, M162, A163, C165, F167, A175,L183, L199, I200, A203, L213, L214, A215, L224, H245, W248, A249, Y251,F252, F255, L256, Y259, L264, A268, V269, A271, C287, L288, F290, F298,I299, L303, L318, M319, L320, A331, V334, A340, I347, A348, V349, H350,A357, L363, L375, F376, A377, A380, C381, V382, W396, Y402, I406, I407,V414, W417, L422, A423, L424, V437, I441, I442, V443, F450, M455, F456,H458, L459, H461, F462, I466, V473, A485, V486, A487, L488, A495, V496,V497, V498, V499, L500, L509, I511, L519, I528, H529, Y531, W533 175Vitamin K-dependent P04070 C105, C131, L212, V227, V228, L229, A240,V241, L242, V248, L249, A251, C254, V263, L265, L280, I300, A301,protein C (EC 3.4.21.69) L302, L303, V339, I363, I365, C373, A388, M406,A408, V417, L419, V434, Y435, V438, I445, I449 176 Cystatin-B P04080A20, V23, L27, F54, I55, V57, V65, H66, L67, V69, L82 177 Trefoil factor1 P04155 C51, C57, C68, F69 178 Major prion protein P04156 I139, Y150,Y157, V161, Y163, F175, V176, C179, V180, I182, I184, M205, M206, V209,V210, M213, C214 179 Superoxide dismutase [Mn], P04179 L38, I42, I46,M47, H50, H54, H55, V59, L62, A72, I82, L88, H98, F101, W102, L105,L117, A120, I121, F131, L135, mitochondrial (EC 1.15.1.1) W147, W149,L150, C164, L170, L179, L180, I182, V184, W185, A188, Y189, Y200, L201,I204, V207, I208, W210, V213, Y217 180 Phosphatidylcholine-sterol P04180V49, I50, L51, V52, L60, A62, A117, V133, V149, L152, V163, A165, A166,Y168, L184, V188, M191, V199, F200, L201, acyltransferase (EC 2.3.1.43)I202, L206, C208, L209, H210, L211, L212, F214, L215, F230, I231, A235,I241, M244, A248, I261, F289, I290, F305, F306, L309, L328, V333, V335,C337, L338, Y339, V372, A373, C380, W383, L396, M404, V405, I414, L418181 HLA class II P04233 C213, V253 histocompatibility antigen gammachain 182 T-cell surface glycoprotein P04234 V33, V35, C37, Y71 CD3delta chain 183 von Willebrand factor P04275 V815, C827, C829, C849,C851, C1272, L1276, L1278, V1279, F1280, L1281, L1282, F1293, L1296,F1299, V1300, M1303, M1304, L1307, V1314, V1316, A1317, V1318, V1319,Y1321, I1329, L1340, A1344, V1347, A1355, V1360, L1361, F1369, A1377,I1380, L1382, L1383, L1384, M1385, A1386, F1397, V1401, L1404, I1410,V1411, I1412, V1414, I1416, A1420, I1425, I1428, F1438, L1440, V1443,L1446, I1453, V1454, L1457, L1497, V1499, A1500, F1501, V1502, L1503,F1514, F1520, M1521, V1524, I1525, M1528, I1535, V1537, V1539, L1540,Y1542, Y1550, I1561, V1565, A1581, L1582, L1585, A1600, V1604, Y1605,M1606, V1607, V1625, V1626, I1628, V1630, I1642, L1657, A1661, V1665,L1666, C1670, L1690, V1692, I1693, L1694, L1695, L1696, F1707, F1713,A1714, F1717, I1718, A1721, V1732, L1733, Y1735, V1743, L1754, V1758,M1761, I1770, A1773, L1774, A1777, L1781, A1795, V1796, V1797, I1798,L1799, V1800, V1808, A1812, A1815, V1822, I1825, I1827, L1836, L1839,L1857, V1861, L1871, C2724, L2786, C2804 184 Argininosuccinate lyaseP04424 L34, V39, A44, Y45, L49, I63, L67, V70, I88, H89, A91, L96, A104,L107, V118, L121, M125, C129, L132, L136, W137, L139, I140, M143, V144,A147, F155, L161, W169, I173, L174, A177, L180, L187, V190, I194, L197,L199, L216, L220, F222, A232, F238, V239, A240, F242, L243, W245, A246,C249, M250, L253, M256, A257, L260, F268, F270, V271, L273, L293, I296,V303, L310, L325, A331, V332, V335, M339, L343, A346, V349, I350, L353,M360, A363, M368, L369, L373, A374, Y375, L377, A387, A390, A394, A398,L405, L413, F420, V424, V434, A444, V448 185 HLA class II P04440 Y36,A46, F47, F53, L54, Y57, A65, F67, F74, W88, L95, V101, C106, L118,V126, L136, L141, L142, V143, C144, histocompatibility antigen, V146,F149, W158, V169, V186, L188, V197, Y198, C200, V202 DP beta 1 chain 186Envelope glycoprotein P04578 A55, V65, A70, M95, V101, M104, I108, W112,V120, C131, I154, I165, L193, H216, A221, A224, I225, G235, C239,gp160/group M subtype B V242, I251, L259, L260, V270, I284, I285, V286,L288, V292, I294, C296, M326, C331, I333, W338, L342, I345, A346,(isolate HXB2) (HIV-1) L349, I359, I360, F361, H374, F376, C378, F383,C385, L390, F391, L416, C418, I423, I424, V430, A433, M434, I449, L452,L453, L454, I467, F468, W479, L483, Y486, V489, I491, V505, I548, V549,L555, L556, A558, I559, A561, L565, L566, V570, I573, L576, I580, L602,A607, I635, I642, W666, W680, M687, I688, V698 187 Receptortyrosine-protein P04626 H42, M45, L46, Y50, C53, V56, L60, L62, L65,F73, L74, I77, V80, Y83, V84, L85, I86, A87, V91, V94, L96, L99, I101,kinase erbB-2 (EC 2.7.10.1) V102, A113, L114, A115, V116, L137, L140,L142, L145, I148, V153, I155, L161, C162, Y163, I172, F173, C204, W205,C227, C240, A241, A242, L304, C331, L345, A355, V356, I361, F364, C367,I370, L374, A375, F376, L397, F400, L403, I406, L410, I412, L422, F425,L428, V430, I431, A440, L443, L445, L448, I450, L453, L455, L461, L465,A466, L467, I468, H469, L474, C475, F476, V477, L494, C504, C520, W521,C540, C576 188 High affinity nerve growth P04629 L103, A110, L117, L122,L138, C215, L249, L251, V254, L258, C265, A267, V282, C300, I301, L346,L348, L361, factor receptor (EC 2.7.10.1) A363, A376 189 Hemagglutinin[Cleaved P04661 I19, C20, I21, V32, V42, V49, F57, C58, I60, I66, L68,C71, F73, A74, W76, I77, L78, C83, L86, W92, Y94, I95, V96, into:Hemagglutinin HA1 Y107, L117, F121, V124, F127, F133, A149, C151, F153,M163, V164, L166, I176, V188, L189, I190, V191, W192, I194, chain;Hemagglutinin HA2 H195, H196, Y207, V214, V216, Y221, M242, F244, Y245,I248, V249, I255, F257, F263, L264, A265, Y268, A269, F270,chain]/strain I272, L280, C294, H308, H311, I315, L327, A347, Y364,A386, L460, L468, H484, C486, C490 A/Duck/England/1/1956 H11N6 190 Heatshock protein beta-1 P04792 V6, F8, L10, V97, L99, V101, A105, V118,I120, V148, L163, V165, A167 191 Cytochrome b-245 heavy P04839 A394,V398, V404, M405, L406, V407, V413, F416, I419, V423, L436, F441, Y442,F454, L458, F473, F520, I532, chain (EC 1.—.—.—) V534, F535, L546 192Insulin-like growth factor I P05019 L58, A61, L62, F73, I91, C95, C100,L105, Y108, C109, A110 193 Fructose-bisphosphate P05062 L16, I19, A20,I23, V24, I30, L31, A32, A33, M40, L44, F59, I62, L63, F64, V66, I70,I74, V77, I78, L79, L84, F94, I97, aldolase B (EC 4.1.2.13) L98, V104,V105, I107, L109, L131, C135, Y138, V143, F145, W148, A150, L152, L162,A163, I164, A168, A170, L171, A172, Y174, A175, C178, L183, V184, I186,V187, C202, V209, L210, V213, A216, L217, L228, L229, V234, Y244, A250,A252, V254, A256, L257, V261, V265, I268, C269, F270, A280, L282, L284,I287, L298, F300, Y302, A305, L306, A308, A310, A313, W314, F328, M329,A332, A334, A338, L357 194 Amyloid beta A4 protein P05067 I34, A35, L41,M43, Y72, C73, V85, I94, W97, C117, C133, W150, A154, C158, C174, F179,V182, F184, V185, C186, C291, C316, C337, V375, L442, L453, Y476, A479,V490, L494, Y497, V498, A500, A523, I537, L548, A555, I558, I666, V669,H684, L688, V689 195 Arginase-1 (EC 3.5.3.1) P05089 I8, I10, I11, A13,F15, V24, V30, L31, L36, L40, V67, V73, A76, L80, A81, V84, A85, V87,L95, V96, L97, H101, L103, A104, I105, I108, H111, H115, L118, V120,I121, W122, V123, A125, I129, L140, V145, L148, L149, L152, I169, A171,I174, V175, Y176, I177, L179, L190, F198, V211, M212, L219, I227, H228,L229, F231, V233, L236, A243, L252, I260, I264, L273, I275, M276, V278,V293, A296, I299, A302, C303, F304 196 Aldehyde dehydrogenase, P05091C36, I39, F40, A48, F54, V68, A69, V76, A79, V80, A82, A83, A85, W93,L104, L105, L108, A109, L111, I112, Y118, mitochondrial (EC 1.2.1.3)L119, A120, A121, L122, L125, L139, V142, L143, C145, L146, Y149, A150,A153, V178, C179, L189, L190, M191, A193, L196, A199, L200, A201, V205,V206, V207, M208, V210, L216, A218, L219, Y220, V221, A222, L224, I225,A228, V234, V235, I237, V238, A245, I249, A250, V255, V258, A259, I270,A273, A274, I293, I294, A303, A307, H308, A310, L311, F312, F313, C318,C319, C320, A321, F326, V327, F335, A343, I370, Y373, I374, F397, I398,V402, F403, V406, I412, A413, I417, V421, M422, I424, L425, F427, I430,V433, V434, L444, A445, A446, A447, V448, F449, L459, A478, F482, L494,L499, Y502 197 Integrin beta-3 P05106 C31, C39, C42, L43, C49, A50, W51,C52, C64, L70, C75, V109, I114, L116, L118, F126, I128, V130, V133,V138, I140, Y141, Y142, L143, M144, L146, M150, I157, L160, L164, A165,M168, I177, F179, A181, F182, V183, Y190, Y192, A198, C203, C210, Y216,L220, L222, F229, V233, F249, A251, I252, M253, A255, C258, I262, L271,L272, V273, F274, I291, M313, Y315, M321, L325, L332, I333, F334, A335,V336, Y344, I351, L359, V366, I370, A373, Y374, V381, L383, L392, A398,C400, I406, L409, C412, L415, V421, F423, I425, A427, V429, F440, I442,L451, V453, V455, C461, C474, C497, C499, C512, C521, C547, C562, C584,C593, C601, C624, V641, C661, C681, C689, V691, F693, L705 198 Integrinbeta-2 P05107 C25, V30, C33, C36, I37, C43, W45, C46, C62, L68, C73,L98, V103, L105, L107, A113, F115, V117, F119, I127, L129, Y130, Y131,L132, M133, L135, M139, V146, L149, L153, L154, A156, L157, I166, F168,F171, V172, F179, V180, C191, C198, F204, F217, V221, I226, L237, A239,M240, M241, V243, A244, C246, I250, V255, L258, L259, V260, F261, A262,I278, Y293, Y301, L307, L311, I316, I319, F320, A321, V322, Y330, L333,I337, A341, L345, V352, I356, A359, V367, L369, L378, Y382, C400, V403,I409, F411, V413, V415, A417, F426, I428, A430, V437, V439, V441, C445,C459, C467, C481, C483, C497, C506, C534, C549, C557, A572, C573, C582,C590, C612, A629, C662, V672, Y674, I687, V689 199 Interleukin-4 P05112L31, I34, L38, L41, C48, I56, F69, C70, A72, A73, V75, L76, C89, H100,L103, L107, L110, L114, A118, L133, F136, L137, L140, M144 200Interleukin-5 P05113 V84, L87, L91 201 Plasminogen activator P05121 V31,A32, A35, F38, V40, V42, F43, V46, A47, V55, V56, F57, Y60, V62, A63,V65, L66, A67, M68, L69, L71, I81, M85, inhibitor 1 I89, M94, A95, L101,L105, I114, A119, I120, F121, V122, L128, F132, F136, F140, V144, V147,F149, A155, I159, V163, I171, L174, L175, V180, L186, V187, L188, V189,A191, L192, F194, W198, F202, L211, F212, M224, M225, F231, Y244, I246,L247, L249, Y251, L256, M258, F259, I260, A261, A262, L270, L273, L277,A279, I282, W285, L296, V297, L298, F301, V307, L309, L313, L316, M318,M321, F329, L332, L338, V340, A343, L344, V347, I349, V351, A358, A363,V364, I365, V366, A368, M377, F381, L382, F383, V384, V385, H387, V393,L394, F395, M396, V399, M400 202 Protein kinase C gamma P05129 L120,V386, A461, I476, W538, L544 type 203 Plasma protease C1 inhibitorP05155 L142, A145, F149, L153, Y154, A168, F169, I174, A175, L177, L178,L193, L197, F213, V218, I224, F225, L230, F236, I262, V266, I274, L278,L281, V288, L290, A292, I293, L295, F313, M325, Y330, A333, A342, V344,L347, L353, L355, V356, M370, L374, L386, M409, M413, L430, M441, H443,L447, L449, V454, A456, A457, A458, A459, A461, L478, F479, V480, L481,F488, V490, F491, M492 204 Complement factor I (EC P05156 C33, V74, A76,C86, F100, V129, I140, A150, V152, A153, C154, A163, C181, L182, V184,C186, L193, A210, C214, 3.4.21.45) C229, C241, C247, L254, C256, C266,I357, C365, I368, I375, L376, A378, A379, L382, I430, A431, L432, I433,A452, C467, L491, M508, C510, A511, L529, V530, C531, V540, W541, V543,V558, V562 205 Alkaline phosphatase, tissue- P05186 L46, A51, V54, I55,M56, F57, L58, A69, A70, L87, M89, A96, A111, A114, A116, Y117, L118,A123, V128, V130, I150, nonspecific isozyme L151, A154, V161, I163,V164, V169, A172, A179, A182, M192, A196, I204, A205, L208, M209, I215,V217, I218, M219, M226, L252, V253, W256, I269, L275, L278, V283, L286,L287, L289, F290, M295, M312, V315, A316, L320, F327, F328, L329, L330,V331, I336, H340, A345, A348, L349, A352, V353, M355, A358, I359, A362,L372, V374, V375, A377, H379, I395, A412, I413, V459, V461, A468, L471,V480, V483, M484, A485, A487, I490 206 Interleukin-6 P05231 I53, I57,I60, I64, L67, A86, L92, C111, I115, I116, L119, F122, V124, Y125, L126,Y128, L129, A140, V143, L150, I151, L154, I164, L179, M189, I194, L195,F198, F201, L202, A208 207 60S acidic ribosomal protein P05386 A8, C9,A13, L16, I28, I32, F47 P1 208 T-cell surface glycoprotein P05540 A222,F224, F226, L239, F255, V262, L283, I285, A293, L298, L300, V311, L313,V314, V315, M316, L326, C328, CD4 V330, L340, L342, I358, W368, C370 209Integrin beta-1 P05556 C27, A32, C38, I39, C45, C64, I114, L119, L121,L123, F131, L133, I143, L145, Y146, Y147, L148, M149, L151, M155, V162,L169, M173, I182, F184, F187, V188, Y195, I196, C213, Y219, F232, V236,F252, A254, I255, M256, V258, A259, C261, I265, V270, L273, L274, V275,F276, I293, Y316, L322, L326, I331, I334, F335, A336, V337, Y345, L348,I352, L360, V367, I371, I372, V382, L384, C415, I418, F426, I428, I430,I445, V454, V456, L458 210 Gag-Pol polyprotein/group P05961 L8, W16,I19, L21, Y29, V34, A37, L41, L50, L51, C57, I60, L61, L64, L75, L78,V82, A83, L85, Y86, C87, V88, I94, A100, M subtype B (isolate MN) I104,W158, V161, V162, F167, V171, I172, F175, A182, L187, M190, L191, V194,A199, A200, L204, I208, A212, I239, (HIV-1) A240, W252, V261, Y265,I269, L273, I276, V277, I285, F296, Y299, V300, F303, Y304, L307, A309,L325, C333, L337, M350, C353, C395, A405, C416, L499, I507, I509, A516,L518, V526, L527, M530, V550, Y553, I556, I558, I560, C561, A565, V569,L570, V571, I578, I579, L583, L584, L591, V603, I624, A626, L627, I630,C631, I640, I643, V653, F654, A655, I656, L667, V668, F670, L673, V683,A691, L693, V699, V701, L702, V704, A707, Y708, F709, V711, L713, F717,A722, F723, I725, I728, Y737, Y739, V741, L742, W746, A751, I752, F753,M757, I760, L761, F764, L780, Y781, V782, L786, H791, I795, L798, H801,L802, L803, F807, F820, W822, M823, Y825, L827, W832, V834, L839, W845,V847, I850, L853, L857, A860, I863, Y864, I867, L872, L876, L888, A892,L896, A897, L903, L918, I919, A920, V922, W930, Y932, I934, L942, A948,A953, V958, L961, A964, V965, I968, I973, V974, F982, L984, I986, W991,W994, W995, A1001, W1003, I1004, W1007, V1016, W1019, I1027, F1033,V1035, A1039, A1048, Y1050, L1062, L1072, A1074, I1075, H1076, L1077,A1078, L1079, V1086, I1088, V1089, A1095, I1099, V1111, I1114, I1115,L1118, V1124, L1126, V1141, V1145, A1161, M1175, A1186, W1214, V1225,I1226, L1227, A1229, V1230, H1231, I1237, F1253, L1254, L1257, A1258,V1279, C1283, L1311, I1314, A1328, V1329, A1332, V1333, I1344, A1349,I1353, A1358, I1361, V1378 211 Collagen alpha-2 P05997 C64 212 T-cellsurface glycoprotein P06127 F33, A35, C44, L48, V50, L52, V59, C60, W64,A77, V80, C81, L90, L92, I105, I106, C107, F114, C125, L128, L130, CD5C132, L133, V289, V291, L300, C301, W312, V315, C316, C321, C350, C360,V365 213 Insulin receptor P06213 L29, C35, I40, L47, L50, C53, V55, I56,L60, M65, L81, M83, I84, L88, L90, V93, L99, L102, F103, L106, V108,I109, A119, L120, I122, M125, L128, L131, L133, L136, V144, I146, L152,I163, L164, C186, C209, W210, C223, C228, C235, C239, C252, A254, F275,W278, C286, V305, L326, I348, A354, L357, C360, I363, L367, I369, I371,L381, L385, I388, I391, Y394, L395, I397, L406, F408, F409, L412, I415,F427, A429, L435, L438, W439, L446, I448, L453, F455, H456, L461, I466,M469, I512, L514, W516, L532, A537, M580, I591, V593, A608, I638, L640,V657, I809, I820, L822, A824, C825, V867, H868, V886, V900, C911, V923,I925, A927, F942, V944 214 Tyrosine-protein kinase Lck P06239 V66, L88,A100, I111, A137, L141, F151, L152, I153, L165, V167, I183, I193, L205,Y209, L216, L220, V240, L245, (EC 2.7.10.2) L247, V270, V272, L275,F285, A289, L295, L300, L303, A305, V306, V307, I312, I314, I315, L324,L328, L341, L342, M344, A345, I348, A349, M352, I355, I361, H362, L365,A367, A368, I370, V372, C378, I380, A381, F383, A386, A408, A411, F417,V423, W424, F426, I428, L429, L430, I433, V449, L453, C465, L469, M473,C476, W477, F487, L490, V493, L494 215 Alpha-galactosidase A (EC P06280W44, H46, C63, I64, L68, F69, M72, A73, M76, W81, Y86, L89, C90, I91,C94, W95, M96, L120, A121, V124, L129, L131, 3.2.1.22) I133, Y134, A135,V137, Y152, A156, F159, V164, L167, F169, L180, Y184, M187, A190, V199,Y200, C202, I219, C223, H225, W226, I232, I239, I242, L243, I253, W262,M267, L268, V269, I270, V281, M284, A285, L286, W287, A288, I289, M290,A291, A292, L294, M296, A307, L311, V316, I319, F337, V339, W340, A348,A350, V351, A352, M353, I354, I367, V369, L372, A377, C378, A381, C382,I384, L403, I407, V413, L414, L415, L417 216 HLA class II P06340 H50,F58, V60, A78, A87, I89, L131, I132, C133, V135, I138, W147, F174, L177,V180, Y187, C189, V191, H193 histocompatibility antigen, DO alpha chain217 Gelsolin P06396 F59, I70, W71, V73, L78, V81, L85, F89, A94, Y95,V96, I97, L98, V101, L112, H113, W115, A127, A128, L135, A143, F157,A173, L189, F190, V192, V198, A200, F210, C215, F216, I217, L218, L220,I224, W227, L238, A240, V243, I247, G254, G264, M270, L271, P276, A279,L280, A282, G283, A292, A298, L300, V303, M310, A316, F321, A322, L326,C331, F332, I333, L334, I342, F343, V344, A358, L359, A362, F365, I366,V377, V379, L380, F389, F392, A434, M439, I449, I452, F468, Y474, I475,I476, Y478, Y480, I489, I490, W493, V526, H534, L535, L538, F539, M544,I545, I546, L565, F566, V568, A578, L588, A593, F594, V595, L596, A602,L604, W605, A610, A618, L621, L622, V632, F641, A644, L645, L657, L669,A671, C672, V680, L693, A694, V698, M699, L700, L701, V707, F708, V709,W710, A723, L724, A727, I744, V747, F756 218 Complement C2 (EC P06681L47, A82, C89, Y107, V113, C144, C151, A160, V173, C191, I462, M573,V697 3.4.21.43) 219 Complement C5 P06684 A691, C703, C728, A731, C735,C736, A739 220 Glycogen phosphorylase, P06737 I16, V25, L28, F32, L36,F54, A55, L56, A57, V60, L64, V83, Y84, Y85, L86, L88, F90, L96, M100,I101, L105, A108, liver form (EC 2.4.1.1) C109, I113, L118, L123, L132,L137, L140, A141, A142, C143, F144, L145, M148, A149, L151, L153, A154,A155, Y156, Y158, I160, Y162, V201, F203, V222, A224, V239, M242, L244,W245, A247, A273, I276, L280, L294, Y298, F299, V300, V301, A302, A303,L305, I308, I309, F317, F327, F330, V334, A335, I336, L338, A344, L345,A346, I347, L350, M351, F354, I357, L360, A365, L368, F373, A374, Y375,V380, W388, L392, V393, L396, L397, H400, I403, I404, I407, I415, L418,M429, L431, I432, I440, M442, A443, L445, C446, I447, A452, V453, V456,A457, I459, H460, V464, F469, F472, L475, I487, W492, L493, L494, A501,L503, I504, Y512, V513, L516, L519, L522, H523, F531, L532, V538, L544,F546, L550, M563, F564, V566, I571, Y574, L578, L579, C581, L582, H583,V584, I585, I591, V604, I605, I606, A610, A611, M616, A617, I620, I621,L623, I624, V627, V630, V631, M636, V637, L641, V643, I644, L646, V651,L653, A654, V657, I658, A660, L663, I667, A670, M680, F682, M683, L684,A687, L688, I690, A696, M700, A701, F712, A729, L736, L739, V742, I743,I746, F759, I762, L766, F772, F775, Y778, Y781, V782, C784, V788, Y792,V802, L803, I806, A807, F812, I818, Y821, A822, W826 221Glucose-6-phosphate P06744 A2, L4, F10, L13, W16, L26, F40, I51, V53,Y55, L59, V60, V64, M67, L68, L71, A72, V77, A79, A80, M84, A97, V98,L99, isomerase H100, V101, A102, L103, I111, V118, V125, M129, F132,C133, V136, I149, V152, I153, I155, M166, V167, A170, L171, V184, I192,L205, F206, I207, I208, A209, F213, A222, A225, F229, A233, A238, V239,H242, F243, V244, A245, L246, V253, F256, I258, F264, F266, W269, V270,Y274, L276, W277, A279, I280, L282, I284, A285, L286, F293, L296, L297,A300, M303, F307, L312, A316, V318, L319, L320, A321, L322, L323, I325,W326, A337, M338, L339, Y341, L345, F348, F352, V379, Y392, I395, C404,F406, L407, I408, F429, L436, M437, A445, L463, I477, F479, L482, M486,L487, A489, L490, V491, A492, M493, Y494, H496, I498, F499, V500, I503,I504, W505 222 Tumor necrosis factor P06804 A93, V95, L127, V137, V141,F143, L154, H156, V158, C179, L204, L210, A212, F230, V232 223Beta-hexosaminidase P06865 W24, Y37, V60, L61, A64, L90, V94, L95, V96,V97, Y116, L118, I120, C125, L127, V132, W133, A135, L136, L139, F142,subunit alpha (EC 3.2.1.52) I156, I161, H169, L172, L173, L174, L181,I186, L190, V192, M193, L198, V200, F201, H202, W203, H204, L205, V206,F211, F216, L221, Y234, V239, V242, A246, I251, V253, L254, A255, F257,L264, W266, L273, V290, F300, M301, F304, F305, V308, F312, L317, H318,L319, F326, W329, I335, M339, L351, F354, Y355, I356, L359, L360, V363,Y366, V371, V372, W373, V376, I389, V391, V398, Y400, L404, V407, A414,L415, L416, W420, L422, F434, Y435, A457, C458, M459, L469, L473, W474,A477, A479, V480, A481, L484, W485, A496, L500, F503, L507, V519 224Thrombomodulin P07204 C369, C388, C390, C413, C439, C464 225 VitaminK-dependent P07225 C212, C241, C265, C267 protein S 226Prostate-specific antigen P07288 I25, V40, V42, V53, L54, V55, V60, L61,A63, A64, C66, I73, L75, F90, V92, L121, L123, L124, L126, L132, A135,V136, C152, A154, F165, V174, L176, C184, C198, A199, L217, C219, L223,I226, L242, Y243, V246 227 Cathepsin D (EC 3.4.23.5) P07339 L71, I83,I85, F92, V94, V95, W104, V105, C117, Y123, L147, V156, F179, F190,F195, I198, L199, M201, V214, F215, [Cleaved into: Cathepsin D L218,F229, A268, W270, V272, L274, V277, V279, L285, A292, V294, M301, V308,L311, A317, I327, I338, L340, light chain; Cathepsin D L342, L349, Y354,F370, L382, L385, V388, F389, I390, Y394, V396, F397, V404, F406, A407heavy chain] 228 Trypsin-1 (EC 3.4.21.4) P07477 I24, V39, L41, L52, W57,V58, V59, A61, C64, I69, V71, L73, V80, L81, F87, I88, I108, M109, L110,I111, L113, I119, V123, I126, L128, C139, I141, W144, C160, A163, C171,A173, Y175, F184, C185, V186, V204, C206, L210, V213, V214, V228, Y229,V232, Y235, V236, I239 229 Decorin P07585 V65, C67, V75, L86, L88, I93,I96, F101, L107, L110, L112, I117, A124, F125, L128, L131, L134, L136,L144, L152, L155, A157, I162, V165, F170, L173, M176, I179, L181, L186,A195, F196, M199, L202, I205, I207, A208, I212, I215, L223, L226, L228,I233, V236, L241, L244, L247, L250, L252, I257, L265, L271, L274, L276,L281, L288, I294, V297, L299, I304, F312, C313, Y324, V327, L329, A352230 Prosaposin P07602 C66, V69, V70, A73, I86, L90, C94, V110, I117,L118, V131, C132, C230, C265, C271, V317, C318, L321, V325, I338, M345,C346, C357, V360, I368, L369, V381, C382, V411, C412, L415, V416, L419,I432, L436, C451, F454, L462, L466, M470, V475, C476, A481 231Beta-hexosaminidase P07686 A55, W57, L70, C91, L93, L94, A97, V124,L127, V129, I131, A139, Y149, L151, V153, A158, L160, A162, V165, W166,subunit beta (EC 3.2.1.52) A168, L169, L172, F175, I189, I194, H202,I205, L206, I207, L214, I219, L223, A225, M226, F228, F231, V233, L234,H235, W236, H237, I238, V239, F244, I249, L254, Y266, V271, V274, A278,I283, L286, F289, L296, W298, L305, I322, L333, F336, F337, I340, F344,I349, H350, L351, F358, W361, I367, M371, L383, F386, Y387, I388, V391,L392, I395, I398, I403, V404, W405, V421, V423, Y429, L433, V436, V443,I444, L445, W449, L451, Y463, Y464, A486, C487, L502, W503, A506, A508,V509, L513, W514, A525, L529, H532, M536, I541, A548 232 UromodulinP07911 C106, C315, V357, F369, A424 233 Proto-oncogene tyrosine- P07949Y30, F31, Y36, L40, V42, L50, V53, L68, L72, L80, I86, L95, L97, L109,V121, L123, V125, A143, V145, F147, C166, protein kinase receptor RetF174, F185, C197, V223, L229, L239, A241, V242, C243, V245, F258, V260,V262, Y263, A269, Y314, F329, L358, L372 (EC 2.7.10.1) 234 Fumaratehydratase, P07954 V62, A70, V92, I93, A95, F96, I98, L99, A102, A103,A104, V106, A117, A119, I120, A123, A124, V127, L138, V140,mitochondrial V153, V156, I157, A161, I162, V175, V181, F191, A194,M195, H196, I197, A198, A199, A200, V203, L207, L211, L214, L218, A220,F225, I228, I229, I231, V240, L242, L244, F248, Y251, V255, A258, I262,M266, I269, L272, A273, A274, A278, F289, V293, A294, V297, L303, A308,L315, A317, H318, A320, L321, L324, M328, A332, L335, I338, A339, I342,L356, L358, C377, M380, V383, A384, V387, M388, V392, V394, V407, M411,M412, I413, V416, L417, A420, L422, L423, F430, C434, V435, V436, I438,A440, I445, M449, L455, L459, A468, I471, A475, L482, A486, L492, F497235 Gap junction beta-1 protein P08034 F51, C60, C64, H73, C168, V170,C179 236 Rhodopsin P08100 V11, Y26, W35, F103, C110, L112, I179, C185237 Beta-microseminoprotein P08118 C38, C57, C60, C62, I67, C84, V97 238Annexin A6 P08133 A26, L29, A32, M33, I43, L44, I47, V58, Y62, L70, I71,L74, L85, I86, V87, L89, M90, A98, I101, A104, I105, C114, L115, I116,I118, L119, M127, L130, A133, Y134, L142, I146, I147, M157, L158, V159,L162, V177, V181, L184, A187, F199, I200, I202, L203, L211, V214, F215,Y218, I226, I230, L241, M242, L243, A244, V245, V246, C248, I249, F256,A257, L260, A263, M264, L274, I275, I277, M278, V279, L284, M286, L287,I289, I292, F293, L301, I305, L317, L318, L320, V338, A339, W343, V357,A369, L372, A375, M376, I386, I387, I390, I401, F405, L413, M414, L417,L428, I429, L432, M433, Y439, A441, W44, A447, M448, A457, L458, I461,L462, A463, I470, I473, A476, Y477, L485, L489, I500, L501, A505, A519,A523, V525, A526, I529, L530, I532, F547, M548, I550, L551, L559, V562,F563, F566, V574, I578, A589, F590, A592, I593, V594, V597, L602, F604,A605, L608, M612, L622, I625, M626, I632, L634, L635, I637, F641, L649,I653, A664, L665, L666, L668, C669 239 Multidrug resistance proteinP08183 A58, M75, L107, M111, Y118, V125, A129, F135, C137, A139, A140,I144, I147, F151, F152, A154, I155, M156, I160, 1 (EC 3.6.3.44) L171,L175, V179, I182, I186, A198, V206, L214, I218, A233, A250, A254, V257,A260, V264, A266, F267, Y277, L281, A284, A292, A301, A302, A308, A311,A313, F314, L332, V334, F335, V338, A348, A358, A362, I365, I369, I375,L392, V397, L410, L413, V417, V423, A424, L425, V426, C431, L439, M440,V451, I458, I461, V463, L466, I470, V473, L479, F480, I484, I488, I500,V504, A507, A509, I513, V524, I539, A540, I541, A542, A544, I551, L553,L554, A557, V569, A572, L573, A576, I583, I585, V592, I598, A599, F601,L615, Y622, I700, C717, A718, I735, I736, L754, L758, F759, L762, A780,L784, L788, V792, F793, M796, L797, L818, A822, V825, A828, A834, A841,L857, A897, A900, I901, F904, V907, F916, A935, C956, A961, L976, V977,F983, A1001, A1005, H1007, I1008, V1035, F1037, V1040, F1042, L1053,L1056, V1060, L1066, A1067, L1068, V1069, V1079, L1082, L1083, V1094,I1101, L1104, V1106, L1109, L1113, V1116, F1123, A1128, I1131, I1145,A1148, A1149, A1152, I1154, Y1165, V1169, A1185, I1186, A1187, L1190,L1198, L1199, V1214, A1217, C1227, I1228, I1230, I1237, I1243, V1244,V1245, L1260, Y1267 240 Mineralocorticoid receptor P08235 C603, V605,V617, C620, C623, F627, A630, C645, I647, A657, C658, C663, M668, L742,A752, L765, L769, L772, M777, W783, A784, L787, F790, L801, W806, L809,F812, L814, L827, A830, L833, F835, C849, I855, F859, L862, L864, F866,Y869, I871, M872, V874, L875, L876, L877, L878, F892, M895, L903, V907,L924, L927, L928, M931, F943, V954, L960, I964 241 Beta-glucuronidase(EC P08236 W45, F47, L68, V99, W100, Y101, V119, V120, I123, A130, V132,L147, I168, I170, A171, I172, L176, F208, Y211, 3.2.1.31) L214, V218,L220, V244, L258, V260, L262, V282, W288, L303, V305, L307, A309, V324,F336, I338, F345, H346, V348, L373, L376, A378, A380, F381, Y386, Y388,M395, V402, V403, I404, C407, L412, H426, M430, V433, A442, V444, M445,W446, V448, A449, A459, L463, M465, V466, V479, V482, A493, V498, I517,L521, F525, I536, I537, Y541, A543, Y561, L565, L566, Y569, L573, V581,L585, I586, F589, F592, V601, I608, F609, A618, A619, L622, Y626 242ATP-dependent 6- P08237 I18, A19, V20, L21, A27, M30, A32, A33, V34,A36, V37, V38, A46, V48, V51, L58, V59, V73, L77, A101, A102, L105,phosphofructokinase, muscle L113, C114, V115, I116, L122, F128, L135,V159, L161, V162, I165, F169, I176, A181, I185, M186, V189, A196, F203,type V204, L205, V207, C212, L215, A216, L217, F229, I230, L243, C244,L247, I260, I261, V262, A263, A266, I279, V283, V284, V293, L296, A307,L312, A320, V321, L324, L325, A333, V335, V336, L348, V358, A370, A389,A404, V405, M406, V408, A412, A413, M415, A417, A418, V419, V423, V433,L434, V435, V436, F440, V456, I481, V494, I495, I496, A501, Y502, L506,C519, F522, V523, V524, I525, A527, V533, V540, A542, A545, C550, C553,A560, V567, F568, I569, I570, C577, L580, A581, A584, L586, A587, I595,L605, V609, L612, M616, L624, V625, L626, I640, Y644, A676, M679, A683,M684, M687, I691, A702, V710, L711, V723, L726, W742, L745 243Neutrophil elastase (EC P08246 I30, V45, L47, A57, L59, V65, M66, A68,A69, V72, A73, A79, V80, V82, L84, I118, V119, I120, L121, V133, A153,M154, 3.4.21.37) W156, A166, L172, V174, C187, L206, V207, C208, I212,I215, A216, C223, A231, F232, A233, V235, I242 244 72 kDa type IVcollagenase P08253 A50, L54, C60, L74, M77, L83, I124, L135, V140, A143,F144, A147, F148, W151, L157, A167, I169, I171, F173, F184, (EC3.4.24.24) A192, F195, F207, L212, W213, V221, V223, Y225, G226, A228,C233, F235, F237, C247, W258, C259, C274, A286, C291, F295, C305, W316,C317, C332, A347, C349, F353, F355, W374, C375, A376, A379, Y381, W387,C390, L397, F398, V400, A401, A402, F405, H407, A408, M409, L411, A419,L420, M421, A422, Y427, L433, I441, L444, I478, A479, I485, F487, F488,I493, W494, A522, V523, Y524, A526, V533, F534, F535, Y543, L556, V568,A570, A571, F572, I582, F583, I606, L617, A619, V620, V621, F631, F632,L640, W657 245 Neuraminidase (EC P08326 I104, V112, V114, F119, V120,F130, F131, L132, L156, V159, A176, W177, A179, A181, C182, M189, V191,V193, 3.2.1.18)/strain A200, V201, A202, V204, L222, C231, I232, Y237,V239, M240, A249, Y251, I253, A256, I261, H273, I274, C277,A/Equine/Kentucky/1/1981 C279, Y280, V286, C288, V289, C290, L302, I304,C316, I319, F349, F351, V357, W358, A359, I363, F371, I373, I374, I393,I394, L397, F406, L418, C421, F422, W423, V424, M426, W437, I443, M445246 Neprilysin (EC 3.4.24.11) P08473 A66, L69, F83, A87, C88, L118,L122, A132, A136, A138, L139, L157, L158, I164, W167, V169, W174, A184,A187, I188, A189, L191, I201, L203, I217, H218, I219, Y231, A244, Y245,F248, M249, V252, A253, I256, M273, V276, L279, I283, A284, A286, M303,L305, A306, I308, L314, I316, W323, F326, I330, M331, I336, V344, V345,V346, A348, Y351, L352, L355, L359, L367, M371, W373, I376, V380, L383,Y387, F394, C411, A412, V415, M419, A422, V423, Y427, V440, I444, I447,V450, F451, L455, A463, A469, A473, A475, L493, Y497, L500, A539, I553,V554, F555, F564, F565, L573, I578, M580, I582, I586, F590, F615, M622,Y626, A634, I649, A650, A658, A661, Y662, L685, F686, F687, L688, F690,A691, V693, C695, A703, I719, L723, F729, C735, M741, V749 247 Integrinalpha-IIb P08514 L34, Y42, F50, L54, H57, I66, V67, V68, A70, V84, C87,L115, L124, V128, I135, V136, A137, C138, A139, W144, V146, A153, V158,C161, L163, A164, A172, Y174, C198, A200, L212, V213, L214, A216, L225,L226, A227, A229, V231, I234, L243, V247, Y284, V285, V286, A288, W291,A297, V298, I300, L301, F320, A325, V329, L337, L338, V339, A341, A354,V356, V359, Y360, L361, L378, F387, A392, L394, L397, I405, A406, V407,A408, V420, V422, L438, A447, F448, Y463, L466, I467, V468, A470, V476,A477, V478, Y479, A481, V485, I518, V522, L535, A537, L539, L541, V552,A581, I596, L598, L600, C633, L662, L664, A675, A681, V682, A688, A693,V715, V716, M724, M734, V736, F750, L752, I754, A775, Y815, L817, V825,L828, I832, V919, C921, M926, V934, L940, L945, L955, A959, V982, L986248 Apolipoprotein P08519 C4145, W4148, C4173, C4184 249 PleckstrinP08567 V26, V27, L28, I33, F35, I48, V68, F69, I71, H79, F81, W92, I96,I100, M133, I140, C155, F156, V161, I162, L165, A181, L184, L190, A200,F209, A215, Y217, F219, L251, F266, L268, A273, L275, H276, I290, L292,L314, F315, I317, L327, A329, W338, I342, A345 250 Collagen alpha-2P08572 L1492, L1518, Y1519, L1531, Y1565, W1566, L1567, I1587, C1590,V1592, C1593, A1595, F1625, H1628, A1630, C1646, F1655, I1656, C1658,C1665, C1705, V1707, C1708, M1709 251 Receptor-type tyrosine- P08575C226, F246, A248, V279, I281, L295, V297, V301, I319, L321, F340, C365,I369, I408, W410, F420, L422, L444, L455, protein phosphatase C (ECL457, A459, A463, M499, V501, L518, V520, F537, F550, A552, F5543.1.3.48) 252 Hepatocyte growth factor P08581 A48, I62, F63, L64, A66,I70, Y71, V72, L73, L78, L130, I131, C133, C141, H144, I154, I161, C175,V176, V177, I193, receptor F195, F196, V197, I214, V216, L219, I235,V237, Y245, I259, Y260, F261, L262, I278, I279, F281, L288, Y291, M294,L296, C298, I299, L300, F314, I316, L317, A319, L329, A330, I341, F343,G344, V345, F346, A347, A354, A361, M362, C363, F365, I367, V370, V383,L386, H388, F389, L424, L429, F430, L439, I442, I452, A453, L455, F462,V465, V467, H476, V477, V486, L503, V504, I505, I510, I513, L515, L518,C520, C529, C541, C561, A573, L581, I583, F588, V603, L622, C624, I638,I640, F652, I659 253 Complement factor H P08603 C21, A48, Y50, V62, C66,C80, V108, A110, C129, C141, V144, C146, V174, F176, M190, C192, C205,Y227, F233, Y235, A249, C251, C325, V347, Y355, I372, C389, F391, L394,V414, L422, V429, C431, Y467, A473, C494, C505, L532, I551, C553, C569,Y587, L593, F595, V609, C611, L636, V655, Y657, I671, C673, C684, Y709,V715, F717, I731, C733, C744, C753, L761, F771, I777, C792, C870, I876,C915, C926, V942, V955, A971, C973, C984, C1048, Y1067, V1073, V1089,C1109, I1120, V1134, Y1136, C1138, L1144, I1150, C1152, C1167, I1169,M1174, I1179, L1181, L1189, V1197, F1199, C1218, L1223, C1228 254 Genomepolyprotein P08617 W91, V106, V107, L110, V117, L121, A127, F129, I131,V135, L147, I148, A150, M151, V152, V202, I207, V209, L213, [Cleavedinto: Protein V227, A229, F231, A306, V326, Y329, F331, L346, A347,C350, W356, L360, L376, C379, V418, A443, I444, I448, VP0/genotype IB(isolate Y450, C451, V465, L471, F600, Y628, V644, V702, I722, Y727,L734, C738, L841, F869, L880, I907, I911, F914, L953, HM175) (HHAV)(Human L954, I962, V1528, V1533, F1535, V1537, M1548, A1550, L1551,V1553, L1558, L1559, V1560, F1576, F1578, V1604, hepatitis A virus(isolate V1605, L1606, M1607, V1609, I1618, I1623, A1631, A1636, L1638,V1639, L1654, V1676, A1679, W1680, M1690, Human/Australia/ A1694, L1695,V1696, I1706, L1707, I1709, A1712, L1718, V1719, A1720, L1722, V1723HM175/1976)) 255 40S ribosomal protein S17 P08708 V9, A13, I17, C35,I50, A51, V54, I61 256 Coagulation factor VII (EC P08709 C141, I213,C219, V228, L229, L230, L242, V248, V249, A251, A252, L264, A266, L268,V285, V288, I289, Y294, 3.4.21.21) I303, A304, L305, L306, V318, L321,L333, V341, W344, A354, V362, C370, M387, F388, C389, A390, H408, A409,H411, L418, I421, V422, V436, Y437, V440, Y443, I444, W446, L447, L450,A463 257 Interleukin-6 receptor P08887 L45, C47, V50, V58, W60, V86,Y94, C96, V130, C132, L148, L149, V150, C176, L178, Y188, V190, M192,V194, L234, subunit alpha V236, L251, F253, L255, Y257, A259, V270,L273, I279, A282, H288, V290, L292, A294 258 Dihydropteridine reductaseP09417 V13, L14, V15, C26, V27, F30, V37, A38, V40, V67, V71, V80, A82,I83, L84, C85, M107, L121, A122, L131, L132, (EC 1.5.1.34) L134, A153,V157, H158, C161, A176, A177, I178, A179, V180, L181, L208, F212, L227,I228, V230 259 Fructose-1,6-bisphosphatase P09467 L14, F17, V18, L34,L38, A41, V42, I45, A52, L74, V82, L86, A91, C93, V94, L95, V96, V106,V115, V116, C117, F118, 1 L121, V133, I136, F137, I139, Y140, A153,A162, A163, Y165, A166, L174, V175, L176, A177, V182, C184, F185, F194,A223, V224, Y227, V250, V253, L257, I262, F263, L264, L278, L279, Y280,C282, M285, A286, Y287, V288, M289, A292, A296, V303, L304, I311, A315,V317, I318, L319, V325, F328, V331 260 Macrophage colony- P09603 C39,I43, L51, L54, F69, V70, L75, C80, A85, V89, M93, L112, L115, L119,C122, C134, L145, V149, V152, F153, stimulating factor 1 L160, F167,C171 261 Platelet-derived growth P09619 L52, C54, V60, W62, L85, L90,C100, Y117, I118, F119, V120, I147, C149, V151, L160, C190, V225, I231,L233, factor receptor beta C235, V237, L265, L276, I278, Y289, C291,V293, I308 262 Pro-cathepsin H [Cleaved P09668 V240, V279 into:Cathepsin H mini chain; Cathepsin H (EC 3.4.22.16); Cathepsin H heavychain; Cathepsin H light chain] 263 Ubiquitin carboxyl-terminal P09936M12, L13, V16, L17, L20, V22, A23, V42, C47, A48, L49, L50, L51, L52,F53, I67, M82, I86, L95, I96, H97, A98, V99, hydrolase isozyme L1 L114,F117, L118, A130, F133, I139, A142, H143, V146, A147, F160, H161, F162,I163, L164, F165, L172, Y173, L175, M179, L193, L194, A197, A198, C201,V212, V217, A218, L219, C220 264 Leukotriene A-4 hydrolase P09960 C8,V16, C17, L22, V28, L35, A39, L41, V43, L53, L55, V65, I67, M87, I89,A94, L95, I103, I105, F107, A115, L116, L119, Y131, L132, F133, C136,A138, C141, A143, L145, C147, V153, Y157, A159, V161, V163, L167, A169,L170, A173, F192, I198, C200, Y201, L202, A204, V206, V207, V221, V228,F235, M241, L242, A245, L248, L259, L260, V261, L262, F266, C275, L276,F278, V279, L283, I294, A295, I298, H300, W302, V307, W312, W316, L317,H321, Y324, L325, H328, I329, A343, L344, L350, L366, L370, V382, F388,A389, L390, L391, F392, L394, L397, L398, F404, F407, L408, Y411, V412,I420, W425, L429, L440, W448, C469, W476, F487, F503, L504, I518, M521,F527, I535, W539, L540, L542, C543, I544, A551, L554, A555, A559, F567,L571, F572, L575, A585, Y589, H597, L603, V604 265 Complement C4-AP0C0L4 L24, L25, F26, V31, L37, V39, V41, L43, V52, V56, L76, L87, A94,L110, V111, A112, I130, L132, I149, Y150, V156, Y158, V160, A162, I174,V176, V178, I215, A217, F219, F231, V233, F241, I252, I266, A268, I271,V276, A280, V282, L286, L305, F319, V340, A341, A343, I345, L378, A382,L386, V390, V403, V405, A407, V409, V431, I433, I435, L444, A450, V462,L473, L491, M508, L510, V529, V533, F541, F543, V544, A545, F546, Y547,V560, A564, L633, V646, F647, L652, F654, I687, C703, A720, C735, A739,F833, L835, L837, L855, L863, V865, V867, V889, V897, V901, V913, V914,A915, V927, L931, V945, L948, V978, V980, A994, L995, V1000, A1001,M1015, I1016, L1018, A1019, A1023, A1024, Y1027, L1028, A1045, I1049,I1056, Y1066, A1067, A1068, W1077, L1078, A1080, V1082, L1083, V1085,L1086, A1089, L1107, F1117, L1132, V1139, A1140, L1141, A1143, F1144,V1145, I1147, A1148, L1149, V1168, A1175, L1179, A1192, A1193, A1194,I1195, A1197, A1199, L1200, A1205, L1210, A1213, L1217, W1230, I1262,A1266, Y1267, A1268, L1269, H1271, A1282, A1285, L1289, V1306, I1307,A1308, A1311, L1327, V1329, L1331, L1358, I1366, V1368, L1378, Y1384,L1501, V1512, V1522, L1524, F1538, A1540, L1578, A1617, Y1625, F1627,V1629, F1643, I1647, F1667, V1669, Y1683, L1684, I1685, M1686, Y1701 266Complement C4-B P0C0L5 L43, I149, I271, L305, V409, L510, A564, L652,I1366 267 Serum amyloid A-1 protein P0DJI8 M35, A38, F54, A56, A62, A72,A73, A99, A100 268 Serum amyloid A-2 protein P0DJI9 A72, A99 269Transcriptional activator P10071 C548, L563, C578 GLI3 270 HLA class IP10321 M29, Y31, A35, F46, V52, F57, V58, F60, A73, W75, V76, Y83, Y91,A95, L102, L105, L119, M122, C125, L127, Y142, histocompatibilityantigen, Y147, I148, L150, L154, W157, A163, A164, A176, A177, L184,C188, V189, L192, Y195, L196, L203, V213, A223, Cw-7 alpha chain L225,C227, A229, F232, Y233, L239, W241, A269, A270, V271, V272, V273, Y281,C283, M285, H287 271 Hemagglutinin [Cleaved P10448 A50, L61, C62, C65,L71, A74, L75, C80, A87, V89, V91, C102, I112, L115, L119, A135, Y143,I145, C151, F161, into: Hemagglutinin HA1 M164, A165, W166, A167, V168,V180, V182, I193, V195, W196, H199, M206, Y210, F218, I251, V253, I266,Y268, I272, chain; Hemagglutinin HA2 L273, L274, V278, A281, I288, C300,L301, H302, A385, A511 chain]/strain B/Bonn/1943 272 Lysosomalprotective P10619 L54, H61, L62, H63, Y64, W65, F66, V67, V78, V79, L80,W81, L82, L91, L94, L95, H98, F101, W117, A121, V123, L124, protein (EC3.4.16.5) Y125, V132, F134, V149, A156, L157, F160, F164, Y167, L172,F173, L174, Y179, A180, I182, Y183, I184, L187, A188, V189, V191, L202,V204, L208, L218, V219, A222, L236, F248, C256, L260, V263, V267, V297,V298, M327, A337, Y340, L341, V346, L350, W359, C362, V366, Y370, M377,Y381, L382, L384, L385, L393, L394, Y395, M401, F411, V412, W426, V428,V441, I447, A448, F449, L450, I452, A455, H457, V459, A466, A467, M470,F471, F474 273 Mast/stem cell growth factor P10721 I54, L56, C58, W66,Y95, C97, I107, V109, V111, F118, V134, C136, I170, I172, V175, L184,C186, V188, F200, L202, receptor Kit V213, F229, V231, C233, I235, W246,A273, L275, A280, F288, C290, A292, V325, L333, V335, Y337, A339, W348,Y362, V374, L377, L382, Y390, F392, V394, F405, V407, V409, C428, A430,A431, W440, V473, V474, V489, C491, A493 274 60 kDa heat shock protein,P10809 A36, M40, V44, L47, A48, V51, V80, A81, A95, V98, V101, A102,A116, V118, L119, A120, I123, A124, I140, V144, mitochondrial A147,V148, A150, V151, L155, V162, I168, V171, A172, A176, I182, I186, A189,M190, F219, F228, C237, A242, V244, L245, L246, I251, I257, V258, A260,L271, V272, I273, I274, A275, V278, A282, L286, V297, V298, A299, V300,A302, L313, M316, A317, A319, V324, F325, L342, V345, V348, I349, V350,L357, L358, I371, I374, A395, L397, V401, A402, V403, L404, V406, V421,A424, A427, A430, A431, V437, L438, C442, A443, L444, L445, C447, I465,I467, I468, L472, A476, A480, I490, V491, I494, A507, M513, I519, A528,L529, A532, A533, A536, L539 275 Thyroid hormone receptor P10828 C107,V109, A114, C124, C127, F131, C151, I153, C164, F166, C169, M174, V225,A228, H229, L246, A268, F269, beta I280, V283, F286, A287, L290, F293,L304, C308, C309, I312, L315, A318, L328, A335, V336, V349, F354, A371,L372, L373, A375, L377, L378, M379, I392, F399, A402, F403, L421, V425,L428, I431, A436, F439, M442, C446, L456 276 Growth hormone receptorP10912 F64, C66, L84, C112, F114, Y125, I127, L129, C140, V143, V147,L160, A169, I171, V173, M188, L194, V217, L220, V228, V230, V249 277 78kDa glucose-regulated P11021 V30, V31, I33, L35, C41, V42, V44, I53,Y65, V66, A67, F68, A80, V92, L98, I99, V108, V119, Y127, I128, V130,A141, protein I145, A147, L150, M153, A157, A159, V165, A168, V169,V170, V172, A174, A183, A187, A191, L193, V195, M196, A204, A205, A206,I207, A208, L211, I220, L221, V222, F223, L225, F230, V232, L234, L235,I237, F242, V244, V245, A246, L253, F258, V262, M263, F266, I267, Y270,V278, A284, V285, L288, V292, A295, L299, A305, I307, I309, Y313, F318,L322, F327, L334, F335, M339, V342, V345, L346, I356, I359, V360, L361,V362, I371, V375, F379, A393, V394, A395, A398, A399, V400, A402, L422,I426, I437, F451, V461, I463, V465, Y466, I487, I497, V499, F501, L509,V511, A513, V542, L565, Y568, A569, L572, M594, A597, V598, L605, F616,L623, V627 278 Hemagglutinin [Cleaved P11132 V5, I19, C20, I21, A25,V32, I35, V42, I48, L49, L57, C58, L60, L66, L68, C71, V73, A74, W76,L77, L78, C83, F86, W92, into: Hemagglutinin HA1 Y94, I95, V96, Y107,L117, L120, L121, F127, I133, A150, C151, Y153, V163, V164, W165, L166,I176, L188, L189, chain; Hemagglutinin HA2 I190, L191, W192, I194, H195,H196, A201, Y207, Y213, V214, V216, L221, M242, F244, F245, I248, L249,I255, F257, chain]/strain F263, I264, A265, Y268, A269, Y270, I272,I280, M281, C290, C294, A300, I301, H308, H311, I315, V322, L327, L329,A/Duck/Ireland/113/1983 A330, A349, M361, Y366, A388, I389, A440, L452,V459, L462, V466, L470, C481, H486, C488, C492, M493, A510 H5N8 279Solute carrier family 2, P11166 I40, Y44, W65, I297, F298 facilitatedglucose transporter member 1 280 Solute carrier family 2, P11168 L10,A17, Y26, V30, I31, I38, Y42, W97, V101, F104, M128, A131, A139, M142,I154, Y164, C165, L171, V172, M174, facilitated glucose Y175, I176,I179, W218, L221, L222, A229, L234, L236, L246, A256, L260, L263, M276,L294, I304, V306, A307, transporter member 2 L310, I322, Y325, I329,F330, V360, F369, M373, M376, C379, A380, M383, A403, I404, F407, V408,I418, M422, V423, A424, F427, A435, A439, V465, F466, L473, I495 281Pyruvate dehydrogenase E1 P11177 A38, I39, M43, L47, V53, L55, V60, A61,I82, A93, I95, A96, A100, I107, C108, F110, F113, A119, V123, A127,V140, component subunit beta, I142, F144, F162, A163, Y166, V174, V175,A183, L186, I187, A190, V197, V198, V199, L200, Y206, F212, A216,mitochondrial I225, I237, V239, V240, V246, A252, A253, L256, C263,V265, I266, M268, I279, V283, L289, V290, I305, I309, A314, I337, I349,I353 282 Integrin alpha-M P11215 F27, F34, V46, V47, V48, A50, L63, C66,A84, M87, L89, L102, L103, A104, C105, C123, F124, I151, A152, F153,L154, I155, I161, M169, F172, V173, V176, M177, L180, F187, L189, M190,Y192, F200, F202, F205, V215, A228, I231, V234, L238, I252, L253, V254,V255, I256, V271, I272, A275, V280, I281, V284, I285, V287, A290, F291,L300, I303, A304, F313, V315, F318, A320, L321, L328, I332, F333, L365,L366, V378, I390, M399, L404, I411, L419, V420, L421, A423, V432, A433,M434, F435, V464, V466, L474, V475, L476, I477, A479, V491, V493, C494,L509, F520, L527, V530, V538, A539, I540, A542, A551, V552, Y553, L554,F555, I571, A572, L580, F583, L601, V603, A605, V609, L612, V617, L618,V631, V657, I670, V674, L680, A689, F691, L714, L716, L718, I729, L731,L733, L748, F764, L792, V794, F800, V802, V804, V806, V818, F820, F822,C864, I881, F883, A889, L895, L897, A899, V925, M951, H953, Y955, V957,L965, I967, L969, F971, V973, L977, I982, W983, L1014, V1020, A1025,C1027, C1032, F1037, I1039, F1043, A1045, L1047, L1051, W1055, L1064,I1066, A1070, I1072, V1097 283 Glycogen phosphorylase, P11217 V16, V25,L28, L36, F54, A55, A57, V60, L64, I83, Y84, Y85, L86, L88, F90, L96,M100, V101, L105, A108, C109, L118, muscle form (EC 2.4.1.1) L123, L132,L137, L140, A141, A142, C143, F144, M148, A149, L151, L153, A154, A155,Y156, Y158, I160, Y162, V201, F203, V222, A224, V238, V239, M242, L244,W245, A247, A273, I276, L280, L294, Y298, F299, V300, V301, A302, A303,L305, I308, I309, F317, F327, F330, V334, I336, L338, L345, A346, I347,L350, M351, L354, L357, M360, A365, V368, C373, A374, Y375, V380, W388,L392, L393, L396, L397, H400, I403, I404, I407, F411, V415, A418, M429,L431, V432, I440, M442, A443, L445, C446, I447, A448, A452, V453, V456,A457, I459, H460, L464, F469, F472, L475, I487, W492, L493, V494, A501,V503, I504, F512, I513, L516, L519, L522, L523, F531, I532, V538, L544,F546, L550, L563, F564, I566, I571, Y574, L578, L579, C581, L582, H583,V584, I585, I591, V604, M605, I606, A610, A611, M616, A617, I620, I621,L623, V624, A626, I627, V630, V631, A636, V637, L641, V643, L646, L653,A654, V657, I658, A660, A661, L663, I667, A670, M680, F682, M683, L684,A687, L688, I690, A696, M700, A701, F712, A729, I736, L739, V742, I743,L746, F759, I762, M765, L766, F772, F775, Y778, Y781, I782, C784, V788,Y792, V802, I803, I806, A807, F812, I818, A819, Y821, A822, W826 284Spike glycoprotein/strain P11224 I16, V44, L79, V87, Y96, I104, A106,V108, L111, A121, I128, F132, V140, I148, A150, V152, C153, I157, C158,C165, A59 (MHV-A59) (Murine F202, H205, A215, F226, Y240, V241, F244,I245, C246, Y258, Y268, L269, F270, I292, V319, C354, F385, F393, V395,hepatitis virus) L411, A414, Y416, Y429, A468, C471, V474, C479, C481,A482, A499, A529, I534, I549, F550, A551, L585, F594, F619, A641, L652,C658, V661, C682, C706, C775, C780, C786, V800, L876, Y891, V900, V906,I912, A931, V952, I956, A980, A994, I998, I1030, A1039, L1046, I1047,A1053, L1054, L1067, A1072, A1075, V1079, I1099, V1103, Y1111, F1112,I1113, H1114 285 Acetylcholine receptor P11230 W141, C151, Y157, C165,V329 subunit beta 286 Ras-related protein Ral-A P11233 H15, V17, I18,M19, V20, V25, L30, F34, V55, L57, V62, I64, I66, L67, A70, I78, F83,F89, L90, C91, V92, F93, I95, F101, F107, I111, V114, V120, F122, L123,L124, V125, L131, V137, A142, A146, A158, V164, V167, F168, L171, M172,I175, M180 287 Medium-chain specific acyl- P11310 A27, A52, F55, A56,I60, A65, I78, A81, M87, I91, C106, L107, I108, L112, A113, C116, V119,A122, M131, I133, Y145, CoA dehydrogenase, L146, M149, C156, A157, C159,I172, I185, I192, W200, Y201, F202, L203, L204, A205, A215, A218, F219,F222, I223, mitochondrial V224, I233, C244, I250, F252, V255, V257,L263, V272, A273, A276, V283, V284, A285, A286, A288, V289, L291, A292,A295, A299, A303, M326, V330, A333, M335, A340, A341, A354, A357, A361,A365, L368, A369, A372, V387, A394, Y397 288 Fibroblast growth factorP11362 L51, L53, C55, V86, V88, C101, F114, V174, F176, C178, I215,M217, V220, Y228, C230, V232, F275, C277, C341, receptor 1 A343, L356289 Glucose-6-phosphate 1- P11413 I33, F34, I35, I36, M37, A39, A44,I48, I52, W53, L55, I67, V68, Y70, A71, F88, F101, Y118, L121, M125,A134, L137, dehydrogenase F138, Y139, L140, Y147, V150, I154, C158,I167, I168, I196, Y197, I199, Y202, M207, I230, C232, V233, L235, I255,I256, V259, M260, L264, L265, M267, L268, C269, V271, A272, M273, V284,Y308, Y322, F337, A338, A339, V340, V341, L342, V344, W349, F354, I355,L356, C358, A361, A367, V369, L371, V391, I392, V394, A399, L440, V444,F452, I464, F465, A492 290 Dystrophin P11532 V25, F29, L40, L50, L51,L54, V77, A80, L81, L84, I99, I111, I114, L140, W143, V144, V156, A168,A171, L172, I173, L196, A199, F200, A203, I228, Y231, I232, L235, Y344,L348, L355, V375, H382, I399, V420, L427, L445, L3053, V3070, Y3073,M3088, L3098, A3109, L3112, L3115, L3119, L3121, A3129, M3145, I3150,C3153, L3154, Y3158, V3175, C3178, L3179, W3181, L3182, L3183, F3199,I3204, L3206, C3207, C3229, L3234, L3238, I3242, I3244, V3263, C3266,W3294, L3295, V3297, L3298 291 C-1-tetrahydrofolate P11586 L20, V24,L38, A39, I40, L41, I53, A60, I63, V81, I85, V94, F97, L98, V114, V124,L135, C152, L155, I156, A168, V169, synthase, cytoplasmic V170, M181,L185, C195, V206, I211, L212, V213, V214, V222, I227, A231, V233, I234,V256, A261, I268, M278, A281, L283, M284, A291, L393, V394, A396, L397,V405, F406, A407, V480, L497, I502, F518 292 Cholesteryl ester transferP11597 A26, V29, A36, A51, V72, I103, V106, V108, I188, I200, I207,F267, L313, V328, V329, A336, C350, F367, V376, protein F380, L426 293B-lymphocyte antigen CD20 P11836 F146, L147, L152, I162, I164, C167,Y182, C183 294 Amyloid beta A4 protein P12023 Y476, A479, V490, Y497,L509, F512, A523, I537, L548, M580, L749, M752 295 Collagen alpha-3P12111 C3112, C3158, C3162 296 Coagulation factor V P12259 V36, A37,A38, V65, Y66, L85, L86, A92, I98, V100, F102, L110, I112, H113, A126,V142, Y150, W152, I154, C167, I171, Y172, L186, I187, L190, I192, C193,L213, L214, F215, A216, F218, V234, V238, I245, V247, I253, W255, H256,L257, L258, F267, I269, H270, F271, L276, L288, V289, A296, M298, W306,I308, H315, M320, I324, I354, A355, A356, Y363, Y391, V394, M395, L431,F435, Y443, Y483, I487, C500, A516, L519, L523, L524, I525, C526, A546,F548, M586, I589, V593, V608, W610, H611, F612, I621, I624, H629, F631,L643, V651, V653, M655, W661, L663, L675, F679, I1584, A1585, A1586,V1618, F1620, I1643, I1648, A1650, I1656, V1658, F1660, Y1668, L1670,H1671, A1672, L1675, Y1677, Y1708, W1710, A1712, A1729, Y1730, L1744,I1745, L1748, I1750, C1751, F1769, V1770, L1771, L1772, F1776, A1807,I1808, L1818, M1820, V1826, L1828, L1830, I1839, H1840, V1841, V1842,F1844, H1845, L1849, L1864, L1872, W1882, L1884, V1888, M1896, F1900,I1902, C1907, L1913, A1937, A1947, W1948, I1963, V1971, F1993, F2032,I2043, L2054, L2056, M2072, A2101, A2111, W2112, A2114, L2123, I2125,I2133, A2135, I2136, C2141, V2150, Y2153, I2155, F2178, I2196, I2201,V2203, I2212, A2213, L2214, L2216, L2218 297 Low affinity P12318 A41,L53, V58, L60, C62, I73, W75, A94, Y102, C104, L117, L120, L124, V125,L126, L131, F133, I139, L141, C143, immunoglobulin gamma Fc H144, V154,F156, F157, F172, A177, Y185, C187, I203, V205 region receptor II-a 298Bone morphogenetic protein P12643 F305, C329, A343, M371, C393, C395 2299 Bone morphogenetic protein P12644 F317, C341, A355, M383, C405, C4074 300 Angiotensin-converting P12821 A46, F49, A57, A86, W97, A101, Y105,L117, I121, L132, M147, L172, L176, L185, L186, A188, W189, W192, H193,enzyme A196, L200, Y204, F207, A214, Y231, L240, Y244, L247, Y251, L254,H255, A256, V258, L262, I271, I277, A279, H280, L282, A287, W290, I293,V297, L306, V308, M312, A319, M322, F323, A326, F329, F330, L333, F342,F366, F372, I374, V388, H389, M392, I395, Y397, Y401, L408, F416, A419,I420, V423, L424, L426, L434, L439, Y453, L454, L455, M457, A458, L459,A463, L465, F467, L470, V471, W474, W492, L495, I502, C503, F513, A515,A517, V521, F531, V532, V535, L536, F538, F540, H541, L544, C557, I559,A565, L569, L573, V584, L585, A596, L599, Y602, F603, V606, A649, F652,Y674, Y700, A704, I717, I720, I721, L732, M747, L770, M774, L783, L784,A786, W787, W790, A794, I798, Y802, Y805, L808, A812, A821, Y829, L838,F842, L845, L848, Y849, L852, H853, A854, V856, A859, L860, I869, I875,A877, H878, L879, L880, A885, W888, I891, V895, A901, M904, A909, M910,M920, F921, A924, F927, F928, L931, F940, L946, V956, F964, F970, I972,L983, A986, H987, M990, I993, Y995, Y999, V1004, A1005, L1006, A1010,F1014, A1017, I1018, V1021, L1022, A1023, L1024, V1026, L1032, L1037,F1051, L1052, M1053, M1055, A1056, L1057, I1060, A1061, I1063, F1065,Y1067, L1068, V1069, W1072, W1090, L1093, L1100, C1101, F1111, A1115,I1119, F1129, V1130, I1133, I1134, F1136, F1138, H1139, A1141, L1142,C1143, H1153, C1155, I1157, A1163, L1167, A1170, M1171, F1175, A1182,M1183, I1186, A1194, A1196, M1197, Y1200, F1201, L1204, L1208 301Cadherin-1 P12830 C163, I178, V188, V204, F205, L214, V216, L220, Y228,L230, A234, M246, I248, I250, V252, F262, V271, V284, A301, M316, I326,V328, Y341, L343, V344, V345, A347, A348, A359, A361, I363, V365, L396,L436, L442, L452, V454, V456, A471, V473, V475, Y508, I542, L548, Y561,A563, I565, A567, L581, L583, I600, I612, I650, L652, I665, L667, L669,M670, L681, V683 302 Xaa-Pro dipeptidase P12955 V18, L22, F23, L30, C31,L34, I45, V46, V47, F71, H72, W73, A74, F75, V77, C82, V85, I86, V88,L95, F96, V97, L136, L144, L145, L176, I180, V185, V194, L195, A205,H206, V209, M210, L222, F226, C243, C245, I267, M272, C273, F275, M277,Y281, F284, A285, I288, F292, V305, Y306, A308, V309, V316, W326, H330,A333, L338, L341, I346, M354, L359, F363, M364, L368, L372, L394, L397,L403, M407, V408, L409, V411, I415, Y416, L422, A425, F443, V449, I451,V455, I475 303 Hemagglutinin [Cleaved P13103 I21, C22, V23, V34, V44,I51, Y59, C60, L70, F75, I79, V80, Y96, L97, L119, L122, F123, I126,F129, I135, C151, F167, into: Hemagglutinin HA1 I177, V189, L190, V191,L192, I195, Y208, V217, M243, I245, I250, I256, F258, F264, L265, A266,Y271, I273, F282, chain; Hemagglutinin HA2 C295, I302, L328, A348, Y365,A387, L461, L469, H485, C487, C491 chain]/strainA/Gull/Maryland/704/1977 H13N6 304 Platelet glycoprotein Ib beta P13224V37, C39, L60, L62, L67, A69, L70, W91, C93, L97, L100, L104, L116,C118, L128, L129, L137 chain 305 C-C motif chemokine 2 P13500 C34, C35,C59, A63, V64, I65, F66, I74, A76, V83 306 Cystic fibrosis P13569 V1240,L1242, L1253, F1257 transmembrane conductance regulator 307 Integrinalpha-4 P13612 Y44, F52, H59, L67, V69, A71, A74, A87, C91, L106, V142,C144, L160, C165, A196, C198, A200, V212, M213, A215, L225, V227, V245,L251, F260, V268, V269, A272, H275, A281, Y282, I283, F284, L291, F306,V313, L315, L323, L324, V325, A327, V339, V341, A349, A366, F368, L375,I378, V386, A387, I388, A390, A399, I400, Y401, Y403, I418, F430, Y445,A449, V450, A452, A458, V459, L460, L461, V466, F502, M519, L521, F535,V550, A562, A579 308 Sodium/potassium- P13637 H34, M36, V41, A58, L94,A98, C101, V125, V130, V161, I162, V175, V176, L180, V181, A191, L193,I195, C201, V203, transporting ATPase subunit F234, C239, A244, V247,V248, A264, I278, A289, A310, I312, F313, I317, L326, V332, A338, C346,V354, C364, alpha-3 L371, M376, A379, M381, W408, A410, L411, I414,A415, L417, C418, A421, V432, A445, L446, V457, L480, I482, H483, Y493,L494, L495, V496, M497, I504, L512, Y532, L535, F545, C546, H547, L550,L573, C574, F575, V576, L578, M581, A587, V589, A592, V593, C596, A599,I601, I604, M605, A614, A616, A618, I623, I624, A635, A636, A650, A652,I678, V679, F680, A681, I691, V692, C695, V702, V709, A714, L715, A718,I720, V722, A723, M724, I739, L740, F745, V752, L757, I758, Y768, L770,F783, L792, I800, A809, L812, L834, V835, L839, A843, I847, Y859, I862,L863, F868, L873, W880, C908, A911, F912, F913, V914, I916, V917, V918,V919, L924, I926, C927, L944, L948, A955, L968, M970, A981, I988, L999,Y1013 309 Delta-aminolevulinic acid P13716 L31, Y33, I35, F36, V37, L50,V53, Y56, L61, L65, V76, L77, I78, F79, V81, A94, A101, A104, I105,L108, L115, V117, dehydratase C119, V121, C122, L123, H129, C132, L134,L150, A151, V153, A154, Y157, C162, V164, V165, A166, M170, M171, V175,I178, L182, V193, M194, Y196, A198, F200, A211, A212, A234, V238, L249,M250, V251, V261, V264, H268, L273, A274, V275, Y276, H277, V278, F282,V300, A303, M304, F307, A310, A312, I315, I316, Y318, Y319, L323, L324310 Tissue factor (TF) P13726 A41, F51, L55, Y66, V68, I70, C89, L91,I95, A105, V107, V155, V157, V159, L175, F179, L183, Y185, L187, Y188,(Coagulation factor III) Y189, F207, I209, V211, F219, V221, A223, V224,I225 311 HLA class I P13747 L26, Y28, H30, F43, V49, F54, V55, F57, M66,A70, W72, M73, Y80, A88, A92, F95, L99, L102, L116, W118, M119,histocompatibility antigen, C122, L124, F137, Y139, Y144, L145, L147,L151, W154, A160, A161, A174, L181, C185, V186, L189, Y192, L193, alphachain E L200, V210, A220, L222, C224, A226, F229, Y230, L236, W238,H245, A266, A267, V268, V269, V270, Y278, C280, V282, H284 312 HLA classII P13765 F33, V34, F43, V50, F52, V53, F56, L60, V64, F66, F73, W87,L94, A100, C105, V117, V125, L135, L140, L141, H142, histocompatibilityantigen, C143, V145, F148, W157, V168, L187, V196, Y197, C199, V201,W214 DO beta chain 313 Electron transfer P13804 L23, V24, I25, I41, A43,A44, V51, C53, L54, V55, C60, V63, A64, L67, C68, V70, V76, A79, L92,L95, I96, I108, C109, flavoprotein subunit alpha, A110, L119, V123,A124, A125, I135, F144, V165, F166, V168, V218, V219, L225, F231, L234,L237, A238, A243, mitochondrial A244, A247, A251, V263, V270, Y275,I276, A277, V278, M290, A298, A305, I307, V323 314 Glycogen [starch]synthase, P13807 V28, L80, Y102, W160, F165, L166, L190, F202, A215,A247, F287, H291, F293, F307, A345, I456, V473, F477, L482, muscle (EC2.4.1.11) C500, V504, L592 315 Endothelin-3 P14138 C107, C169 316Macrophage migration P14174 P2, F4, V6, F19, L23, L27, C57, A58, L62,Y76, L79, L80, L83, L84, L88, I90 inhibitory factor 317 Folate receptorbeta P14207 A34, C51, W54, A58, C59, C60, M86, C90, F94, C99, L100,C103, V126, L128, C129, C133, W136, C140, F176, L182, C183, L186, C203,I204, M206, V219, A220 318 Hepatocyte growth factor P14210 I39, F42,L50, C70, A71, C74, L80, C84, A86, F87, V88, C96, W98, F99, F101, F112,L118, Y136, C149, W152, L172, C177, C189, F190, C206, Y219, C232, W235,C260, W270, C271, Y272, C283, I285, C288, Y313, W329, C354, W364, C365,F366, C377, I380, C383, V495, M508, V509, L511, C519, L523, V529, L530,A532, C535, Y544, A546, L548, I550, L579, V580, L581, M582, L584, V594,I597, C612, V614, L629, A632, L634, C642, I657, C658, A659, C669, L677,C679, V687, V690, I691, F706, V709, A713, I716 319 Perform-1 P14222 V61,L249, F442 320 D(2) dopamine receptor P14416 V78, F189 (Dopamine D2receptor) 321 Solute carrier family 2, P14672 L24, A27, A31, Y40, V44,I45, I52, Y56, W81, V85, A86, F88, I99, M112, A119, M126, A129, L138,I145, Y148, L155, facilitated glucose V156, M158, Y159, V160, I163,A187, W202, L205, L206, V210, A213, V218, L220, L230, A240, L244, L247,L260, transporter member 4 L278, L288, I290, A291, L294, A305, V306,Y309, I313, F314, V344, H353, L357, M360, C363, A364, M367, A370, A387,I388, F391, V392, I402, I406, V407, A408, F411, A419, A423, V449, F450,L457, I479 322 Platelet glycoprotein IX P14770 L93 323 Interleukin-1receptor type 1 P14778 I39, W57, H75, L81, F83, A86, C96, V97, V98,C104, I107, A111, L140, C142, M145, F148, W160, L181, V183, Y194, C196,A198, I209, I213, F215, V238, L246, C248, V250, W260, L296, I298, I301,F305, F310, C312, F313, A314, L327 324 Matrix metalloproteinase-9 P14780A45, L49, L74, L78, C99, I121, I137, A140, F141, A144, F145, W148, L154,A164, I166, I168, L187, A189, H190, A191, F192, A202, F204, W210, V218,P219, F222, A225, C230, F234, G238, C244, W255, C256, C271, A283, C288,F292, C302, W313, C314, A315, C329, C347, F351, F353, W372, C373, A374,F379, W385, C388, L395, F396, V398, A399, A400, F403, H405, A406, L407,L409, A417, L418, M419, Y420, F425, L431, I439, A515, A523, L531, L533,F534, I556, F580, F581, F582, V587, L604, V613, L626, F627, F635, F673,C674, Y679, L702 325 Interleukin-2 receptor P14784 C36, Y38, A42, I44,C46, W48, V61, A63, L88, L98, V101, V104, L106, V108, F124, F127, L130,L132, C148, I150, F167, subunit beta A169, F206, V208, V210 326Gamma-aminobutyric acid P14867 V416 receptor subunit alpha-1 327 ProteinC-ets-1 P14921 A323, A327, F340, L341, L342, L345, C350, I354, F363,L365, V371, A372, L389, L393, I401, I402, V411, F414, L418, L429, L433328 Junction plakoglobin P14923 A140, A162, A163, V166, A174, L179,L185, V186, A188, V189, V190, M193, L209, L212, L219, I222, I228, A230,L231, V232, V242, A246, I247, L250, L253, A260, V264, L270, M273, F284,L285, A286, C291, L292, L295, A296, I306, A308, L315, V316, I318, M319,L327, V334, L335, L338, C341, I348, V349, A351, M354, A356, L357, L361,L368, V369, C372, L373, L376, L379, V382, A383, L389, V392, L393, L396,V397, L400, L408, C410, A411, L415, L418, V429, V435, L438, I439, A441,A445, I451, A455, V456, A458, L459, L462, A472, V476, I485, V486, L488,L489, L497, V498, A500, I502, L504, I505, L508, A509, L510, A513, A516,L518, V523, I524, L527, L530, L531, A534, M556, I559, V560, C563, A566,L567, L570, A571, I580, I586, L588, F589, V590, L592, L593, I600, A604,A605, V607, L608, L611, A612, A618, A620, I621, A623, A626, L630, L633,L634, A642, A645, A646, V648, L649 329 Leukemia inhibitory factor P15018L44, I48, L52, L55, A59, L62, Y66, F74, L81, C82, L102, L105, Y106,I108, V109, V110, L112, L116, I119, A130, L133, L137, L144, L147, L148,V151, L152, C153, L155, C156, V164, C185, L187, L188, Y191, I195, L198330 Phosphoglycerate mutase 2 P15259 L6, V7, M8, V9, H11, F22, A28, A38,A42, A44, I45, F52, I54, C55, Y56, L60, A63, L67, I70, L71, L87, H91,L95, V112, (EC 3.1.3.13) M126, I136, Y142, L156, I160, A163, W167, I171,I175, A177, V181, L182, I183, A184, A185, H186, L190, I193, V194, L197,I205, L210, I214, I216, V217, Y218, L220, V239 331 Interferon gammareceptor 1 P15260 V46, W48, F59, V61, V63, C85, I87, L98, V100, V102,A104, A120, I141, I143, I145, Y172, V174, V176, I187, C200, C214, V215,A217, I238 332 Arylsulfatase A P15289 I23, V24, L25, I26, F27, A28, L31,L36, L49, Y63, V64, A74, A75, L76, L77, L100, V107, A108, L111, Y116,M120, A121, W124, L126, I147, Y149, H151, C156, C161, V177, I179, L181,L182, A189, L194, L197, Y201, A205, L208, M209, A212, F219, F220, L221,Y222, Y223, A224, H226, H227, F238, F247, L251, L254, A257, V258, L261,I265, L275, V276, F278, A280, V310, A314, L315, A331, L337, L340, A341,A344, L358, F375, Y376, V386, F387, A388, V389, Y394, A396, H397, C414,H415, P426, L428, L459, C500 333 Beta-1,4- P15291 V154, V178, A179,I180, I181, I182, F184, L191, W194, L195, L198, H199, V201, L202, L207,Y209, I211, Y212, V213, galactosyltransferase 1 I214, A225, L227, L228,V230, A235, Y241, F244, V245, F246, L251, I252, Y260, H268, I269, A272,V289, A291, L292, F297, I300, F303, W308, W310, I317, L321, M366, L367,Y376, L386, V392, I394 334 V-type proton ATPase P15313 V47, V52, V53,L54, V57, V66, F68, V80, V83, A88, I89, V90, V92, C106, V117, M121,V125, F126, I147, M163, I164, subunit B, kidney isoform I168, I171,V173, I177, A178, I183, I185, F186, A188, I196, A197, A198, I200, C201,A204, L206, V207, H217, A222, I223, V224, F225, A226, A227, M228, F238,F242, V251, C252, L253, F254, L255, I266, I267, L271, A272, L273, A276,F278, L279, A280, V287, L288, V289, I290, L291, M294, Y297, A298, A300,L301, V304, A306, A307, M321, L325, I328, Y329, A332, V335, I342, I345,I347, L348, I359, F365, I371, V373, L377, I386, V388, A399, H409, V412,L416, C419, Y420, V426, F448, L449, F452, F456, I457, V467, L471, W475,L478, F481 335 Folate receptor alpha P15328 C37, L53, C57, W60, A64,C65, C66, W86, M92, C96, F100, C105, L106, C109, V132, L134, C135, C139,W142, C146, C152, W156, F178, F182, L188, C189, I192, Y197, I210, M212,V225, A226, M233 336 B-lymphocyte antigen CD19 P15391 L36, C38, W52,F83, V87, F94, L96, C97, V113, L188, L196, L198, C200, W214, L225, L228,W240, L246, L248, W281, W283, L284, W290 337 Granulocyte-macrophageP15509 L47, C60, L62, C81, F94, V96, I128, M134, C136, Y150, L152, C178,F192, V194, C233, W237, F251, Y253, L255, V257, colony-stimulatingfactor L270, V294, I296, A298, A299 receptor subunit alpha 338 Membranecofactor protein P15529 C80, A93, M123, F125, L139, C141, A148, V160,V187, I208, C210, V226, V252, I268, C270, C283 339 Vascular endothelialgrowth P15692 C52, I61, I72, F73, V78, L80, L92, I106, F122, C213, C225factor A 340 Immunoglobulin lambda- P15814 W67, C82, V97, L104, V106,L107, V116, A128, A131, L133, C135, L136, M137, F140, Y141, L145, V147,W149, A151, like polypeptide 1 A174, A175, L179, L181, Y192, C194, V196,H198, V203 341 Arylsulfatase B P15848 L47, V48, F49, L50, L51, A52, L55,V60, L72, V80, Y85, Y86, L98, I105, V122, L128, L132, L133, M142, V143,W146, L148, C155, Y168, L169, Y175, H178, I184, A193, F196, F215, A219,L232, F233, L234, L236, A237, L238, V241, Y255, Y266, A267, M269, V270,M273, V277, V280, L284, V294, F295, I296, F297, L321, V326, V329, F331,V332, I348, H349, I350, L354, L357, A361, V376, I380, I389, L391, L392,A431, A432, I433, L440, L441, C447, L474, F475, L498, L502, W529 342Beta-galactoside alpha-2,6- P15907 L109, L144, F160, W165, A178, C184,A185, V187, L193, I202, A207, V208, L209, A214, V223, I229, L231, M232,sialyltransferase 1 F243, L254, I255, V256, W269, F277, Y281, Y284,F293, I295, L296, M300, L304, L308, M325, L326, I328, I329, I330, M331,M332, C335, V338, I340, Y341, L344, Y369, L378, V379, L382, I390, L392,A396, L398 343 Desmoplakin P15924 C191, M195, V214, I228, L235, A247,L251, Y255, L258, I275, F312, A343, I347, I364, C367, I368, H371, F381,A385, Y403, L414, L421, V446, L463, C467, V476, C482, W493, V495, V508,L510, I512, A519, I526, M544, L547, C553, I560, A562, L568, V623, V1975,A1977, L1980, C1983, V2004, I2018, A2019, A2021, L2031, A2034, L2048,A2051, A2053, A2054, I2058, V2069, A2072, I2086, A2089, A2092, A2110,M2122, L2124, L2125, A2127, V2134, V2141, F2142, L2143, A2148, F2172,Y2183, L2186, L2201, V2217, L2222, I2250, I2260, A2261, I2263, A2277,A2288, L2292, A2294, A2296, A2297, I2301, V2312, A2315, L2329, A2332,V2336, Y2339, A2353, L2367, L2368, A2370, I2377, H2384, L2386, A2391,F2415, L2424, Y2426, L2429, L2443, L2444, I2619, A2621, I2622, I2631,L2650, L2651, A2653, C2656, I2660, L2671, A2674, V2679, L2688, A2691,A2694, A2709, A2712, F2726, F2729, L2736, V2737, A2750, L2774, I2783,Y2785, A2788, A2805 344 Mucin-1 P15941 I1049, F1054, L1058, Y1065,Y1066, L1069, F1086, F1094, V1099, F1107, L1134, V1141 345 P-selectinP16109 W42, W53, C60, L67, V68, A69, L79, Y90, W91, I92, I94, A114,A118, C131, V132, I134, I136, W145, A156, L157, C158, C168, C194, C226,C244, C288, F290, C306 346 Integrin beta-4 P16144 L1544, V1546, Y1560,V1562, I1577, V1587, F1598, V1600, A1602, I1618 347 Toxin A (EC3.4.22.—) P16154 L9, A13, Y23, I26, L27, L30, L36, Y45, L48, L51, I55,F58, M59, L71, L74, I78, V82, L97, H98, F99, V106, A110, Y113, W117,L128, W129, A134, F135, L136, V137, L140, A143, I144, A152, L156, F170,Y171, M175, I178, Y179, F185, I201, I204, I205, H208, L209, I231, I239,L244, F245, I253, Y254, L258, L259, A266, A267, I270, V271, L273, L274,A275, L276, V282, Y283, L284, M288, L289, I314, L316, A318, I319, F334,F345, I349, I358, F359, L362, V367, L370, I372, I374, A375, A385, L386,I387, L394, V398, V402, Y406, L409, L413, A416, F423, F430, L434, F445,L446, I449, L453, F457, A461, L467, A472, Y473, A476, Y477, F480, L483,L497, F500, A526, L561, V580, Y582, I583, I584, C597, F600, I608, I609,I610, Y636, I638, L642, V648, V650, F652, I653, F665, L673, I677, F680,I684, I688, V693, V695, L697, C700, M702, F703, Y713, L717, L718, I721,I725, L729, V732, I737, I739, A741, L756, I764, A769, I770, I780, A791,I806, L857, V867, L871, L885, I886, F888, V900, F902, I903, F920, Y923,I927, L961, F965, I967, V987, V989, L991, A993, L1000, I1003, L1009,A1016, L1050, V1068, A1078, I1084, V1122, Y1125, F1126, L1129, L1152,V1153, I1154, C1169, I1171, A1173, I1204, M1222, L1224, A1227, F1232,L1253, I1256, F1264, I1276, L1279, I1288, I1290, F1299, I1304, F1317,Y1324, L1326, L1328, I1333, I1337, L1339, W1345, I1346, F1347, V1353,L1383, I1390, L1405, I1413, L1415, I1416, I1417, I1419, L1430, L1441,I1448, L1451, I1458, A1473, I1474, I1482, L1493, F1503, F1516, M1517,I1524, I1538, F1540, I1542, V1550, V1552, L1555, L1557, V1561, Y1565,V1569, M1582, F1585, L1586, F1591, L1594, F1608, L1610, V1611, F1621,F1633, F1646, V1653, V1654, V1655, L1671, Y1675, L1678, V1688, L1689,I1690, Y1695, I1701, I1714, I1728, L1730, W1739, F1746, I1768, L1769,F1782, L1790, I1793, F1864, L1872, F1883, F1905, A1906, F1936, F1956,A1961, A1963, A1964, V1965, F1977, F1998, F2006, F2017, F2039, A2040,F2070, F2090, A2095, A2097, A2098, Y2109, Y2110, F2111, F2132, F2151,F2153, I2158, I2161, F2173, A2174, F2204, F2224, A2229, A2231, A2232,Y2244, F2245, F2263, F2265, F2287, A2288, F2318, F2338, A2343, A2345,A2346, I2352, Y2357, F2359, F2380, F2399, F2401, I2406, I2409, F2421,A2422, L2445, F2452, F2472, A2477, V2478, A2479, V2480, Y2492, F2493,F2512, F2514, F2534, A2535, F2565, F2585, A2590, A2593, I2599, F2604,Y2605, F2606, F2625, A2626, F2656, F2676, A2681, A2683, A2684, A2685,I2691, F2697, F2698 348 Beta-galactosidase (EC P16278 F41, I51, I55,H56, Y57, W65, L69, M72, A75, A79, I80, V84, W86, H89, V104, F107, L108,A111, H112, L116, V118, 3.2.1.23) I119, L120, Y125, I126, A128, W130,M132, L135, A137, L139, L140, L146, L147, Y154, V158, W161, L162, L165,L166, M169, L172, L173, V180, I181, V183, Y189, Y199, L200, L203, F207,V215, F218, L228, L236, Y237, V240, A251, F269, V289, L293, I296, A301,V303, L305, M307, F308, I309, A320, L337, A340, Y347, L350, I353, I354,A387, A388, L392, F406, F415, V416, Y418, C426, L432, V439, A443, V447,L455, I465, A471, L473, L475, V477, V483, I489, L495, L499, L501, W509,I511, A519, L524, A550, F551, I558, I571, F573, V581, W582, I583, L588,Y591, L601, V603, I616, V618, A624, A635, V636, F638 349 Histone H1.5P16401 I47, L65, I83, L87, L90, L96 350 Cytotoxic T-lymphocyte P16410V40, A48, A54, F56, C58, Y60, A66, V69, V71, V73, C85, A86, A87, L95,V112, L114, I116, Y127, C129, V131, I149, protein 4 V151 351 Epithelialcell adhesion P16422 Y32, C48, C66, V68, A122, I144, H150, L162, L176,F180, L185, I191, L195, V207, I209, A213, Y215 molecule 352 Histo-bloodgroup ABO P16442 A92, I94, I116, L118, V120, A122, I123, L130, F133,L134, A137, F141, M142, H145, V147, H148, Y149, Y150, V151, systemtransferase F152, M189, M191, I192, F195, C196, F200, V204, Y206, L207,V208, C209, V210, V212, M214, F216, V220, V222, I224, L225, L228, F229,L232, A254, I256, Y264, Y265, L266, G268, F269, F270, V274, V277, L280,C284, M288, V290, A298, H305, L306, L310, V318, L319, Y323, L324, W325,L336, L339, F341 353 Thyrotropin receptor P16473 C41, L57, L59, L64,I67, F72, I78, I81, V83, L89, L92, F97, V103, I106, I108, L114, A121,L122, L125, L128, L131, I133, L144, V147, F154, L156, I158, M164, I167,L175, L180, L182, L184, F189, V192, A196, F197, V205, L207, L213, A220,L231, V233, L252 354 Interleukin-7 receptor P16871 L55, C57, I73, Y92,I107, V109, L123, V127, F146, V148, V160, V167, A168, I203, V205 subunitalpha 355 Fumarylacetoacetase P16930 L17, V21, F22, I32, V34, A35, I36,I40, L41, L43, I46, F50, L55, F62, L67, F70, M71, A77, A81, L85, L89,L96, L102, A106, L196, M198, L200, M202, A203, F204, F205, V206, A221,M228, V229, L230, M231, W234, A236, V259, V263, V264, A268, L269, L287,F295, I297, V301, L303, C315, W324, M326, L327, L330, L345, L346, A347,I351, M362, L375, V390, I392, C396, I403, F405, C408, V412 356 Alpha-N-P17050 W30, A32, C49, I50, L54, F55, M58, A59, M62, W67, Y72, L75, I77,C80, W81, L91, I102, L105, A106, V109, L116, I118,acetylgalactosaminidase Y119, A120, M122, V138, A142, F145, V150, L153,L155, Y169, M172, A184, F185, C187, L205, C209, L211, W212, (EC3.2.1.49) I218, V225, I228, L229, L239, V242, W248, M253, L254, L255,I256, A268, M270, A271, L272, W273, V275, L276, A277, A278, L280, M282,I296, L297, M302, I305, I324, V326, Y327, A337, L338, V339, F340, F341,L355, I365, A368, F386, I390, M397, L400 357 Aspartate aminotransferase,P17174 V34, L36, L51, V53, V54, V57, F80, A84, A88, A95, V104, A112,L113, I115, A117, L120, A121, V134, V136, H144, cytoplasmic F148, F174,L178, A181, I186, V187, V188, L189, A193, H194, I209, A210, M213, F221,F222, A238, A240, I241, F244, F251, C253, A254, F257, F261, V268, L271,M288, V292, A304, I306, V307, A308, W320, V324, M327, A328, L338, L342,I354, M360, F361, L374, I380, L382, I388, V390, L393, L398, V401, A402,A408 358 HLA class I P17693 M29, Y31, A34, A35, F46, A48, V52, F57, V58,F60, M69, A73, W75, V76, Y83, A95, L102, L105, L119, W121, M122,histocompatibility antigen, C125, L127, Y140, Y142, Y147, L148, L150,L154, W157, A163, A164, V176, A177, L184, C188, V189, L192, Y195, alphachain G L196, L203, V213, A223, L225, C227, A229, F232, Y233, L239,W241, A269, A270, V271, V272, V273, Y281, C283, V285, H287 359 Neuronalacetylcholine P17787 V56, L60, L83, W87, L119, A135, V137, I143, W145,A149, F173, I183, L185 receptor subunit beta-2 360 ATP-dependent 6-P17858 I18, V20, L21, A27, M30, A32, A33, V34, A36, V37, A46, V48, I51,L58, V59, V73, I77, A101, A102, L105, L113, C114, phosphofructokinase,liver V115, I116, L122, F128, L135, A159, L161, V162, I165, F169, I176,A181, I185, M186, I189, A196, F203, V204, L205, type V207, C212, L215,A216, L217, F229, I230, M243, C244, L247, I260, I261, I262, A263, A266,V279, V283, V284, V293, L296, A307, L312, A320, V321, L324, L325, A333,V335, V336, L348, V358, A370, A389, A403, I404, L405, V407, A411, A412,M414, A416, A417, V418, V422, V432, Y433, V434, V435, F439, V455, I480,L493, V494, V495, A500, Y501, L505, A510, C518, M521, C522, V523, I524,A526, V532, L539, A544, M549, C552, A559, V566, F567, I568, V569, C576,L579, A580, I585, A586, V594, L604, V608, M611, M615, L623, V624, L625,L639, Y643, L678, A682, M683, L686, L690, A701, V709, I710, V722, L725,W741, L744 361 Ganglioside GM2 activator P17900 L80, C106, C136, C183362 Complement receptor type 1 P17927 C43, A52, L69, I84, C86, C99,I121, I127, Y129, A143, C145, V152, I164, C166, V191, Y193, I213, C215,C238, F256, V262, V278, C280, C493, I534, I571, I577, C595, V641, C665,C688, F706, V712, V728, C730, C943, I984, C986, C1004, I1021, I1027,A1043, C1045, A1052, I1064, C1066, V1091, Y1093, C1095, I1113, C1115,C1138, F1156, V1162, V1178, C1180, C1396, I1437, V1480, C1498, V1544,C1568, C1591, F1609, I1615, V1631, C1633 363 Vascular endothelial growthP17948 F135, M148, L154, I156, C158, V160, V167, L169, F192, I194, A197,L205, C207, A209, Y220 factor receptor 1 364 TFIIH basal transcriptionP18074 L40, M42, L53, A54, M57, A58, L70, Y72, C73, I80, V83, I84, L87,L102, L107, A108, L109, L115, A139, L170, L177, factor complex helicaseC190, Y192, L194, A195, A202, Y209, V231, V232, A236, I239, C243, L251,L256, C259, L263, A298, V309, C375, XPD subunit (EC 3.6.4.12) L382,A404, L406, C437, A443, I444, I455, I456, L461, L471, F473, M493, I494,Y520, A537, F539, I561, Y584, A594, L596, L597, V599, A617, I619, M620,F621, V623, A635, A656, A660, V664, A667, M677, V678, F684, W696, A704365 Toxin B (EC 3.4.22.—) P18177 L9, A13, Y24, I27, L28, L31, M37, Y46,L49, I52, Y59, L72, F75, L79, V83, L98, H99, F100, I107, Y114, W118,V129, F130, A135, F136, L137, I138, L141, V145, A149, F171, F172, M176,I179, F186, I202, I205, V206, L210, I232, V240, F246, L254, Y255, L259,V260, W263, A267, A268, I271, L272, I274, A276, L277, M283, Y284, L285,M289, L290, L317, A319, I320, F335, F346, L350, I359, F360, L363, A368,L371, V373, I375, A376, L387, I388, C395, I399, I403, Y407, L410, L414,A417, F431, I435, M447, L450, L454, F458, V462, L468, A473, Y474, A476,A477, Y478, L481, F484, L498, F501, A527, L562, I578, Y580, I581, V582,A594, C595, F598, A599, V606, L607, F608, A618, Y634, I640, I646, L648,F650, F663, L671, I675, A678, A682, I686, I691, I693, L695, M700, F701,Y711, L715, L716, V719, I723, M727, I730, I735, V737, A739, L754, I762,I778, V789, F1866, F1888, F1908, A1909, F1938, H1956, F1958, F1979,F1999, F2019, F2039, A2040, F2069, F2090, A2095, F2305, A2306, F2335,F2355, A2360 366 Vinculin P18206 F4, H5, I9, L13, A17, I20, L70, M74,A77, V81, C85, A91, A92, L95, A104, I109, L116, L124, A129, V131, I134,C138, L145, A148, Y160, L164, M171, I175, L182, L191, V192, V198, L201,L205, A208, M209, V213, I223, A226, M237, I241, I244, V247, L248, A269,I273, A280, W283, A298, I299, I302, A306, I321, V335, A353, L360, L363,V367, I384, I388, A391, I408, A411, A415, A419, I431, I438, L445, V466,L470, L473, A480, A500, A518, C545, V548, L551, L576, L580, L609, A613,F626, F633, A644, A679, L683, F695, L734, A760, I763, V766, V783, A786,L790, V828, V831, A909, M956, I966, A970, L973, A977, I987, I988, A990,A991, M994, A995, M998, M1001, L1015, C1018, A1019, I1022, A1023, A1025,V1029, A1033, A1037, C1040, L1049, V1052, C1053, I1056, L1063, A1071,A1087, L1091, A1095, L1098, M1099, V1102, V1106, A1109, A1112 367Interleukin-1 receptor P18510 F38, I40, V56, A57, V73, A80, L81, F82,L83, C91, L92, C94, L103, F123, F125, F136, C147, A149, V156, L158, F171antagonist protein 368 Cytidine deaminase/strain P19079 L6, A10, A13,A28, A29, L30, L31, A54, A58, L59, A62, L73, A74, V75, A76, A77, C89,I93, V101, V103, V104, V117 168 369 Erythropoietin receptor P19235 A39,L41, L42, L50, C52, F53, L60, C62, F63, W64, F79, Y81, L83, F105, C107,L120, L122, V124, I139, V142, V143, L144, L145, V152, V162, L164, W166,I178, Y180, V182, V184, L207, F218, A219, V220, A222, M224 370Lymphocyte function- P19256 F43, V54, W56, V63, A64, L90, I92, L95,Y103, F116, L118, L121, L129, C131, V140, M156, M163, C166 associatedantigen 3 371 Vascular cell adhesion P19320 A37, V43, L45, C47, L80,M82, V85, Y93, C95, A97, I108, F115, I133, V135, C137, V139, V142, F145,I150, L152, L178, protein 1 L193, C195, A197, L199, A325, V331, L333,C335, L368, L370, V373, Y381, C383, V385, I396, F403, V421, V423, C425,V427, V430, L433, I438, L440, L466, L481, C483, A485, L487 372 Tumornecrosis factor P19438 C59, C62, C72 receptor superfamily member 1A 373Hemagglutinin [Cleaved P19694 I25, C26, M27, V38, V48, L54, V55, L63,C64, L70, C76, I78, I79, A82, L83, C88, L91, V98, F99, I100, V106, C109,Y110, into: Hemagglutinin HA1 F112, Y117, L120, L124, A125, F130, F137,A150, C151, F159, F160, L163, L166, Y191, W193, V195, H196, H197, chain;Hemagglutinin HA2 Y208, V215, V217, I243, F245, Y246, I249, V250, L255,I256, F258, L264, I265, A266, Y271, I288, C295, H296, V302,chain]/strain V323, L330, A331, A348, W357, Y365, A387, A439, L461,L469, C480, F481, I483, H485, C487, C491, I492, I495,A/Budgerigar/Hokkaido/1/1977 A509 H4N6 374 Nuclear factor NF-kappa-BP19838 F57, L69, V84, A93, V95, I96, V97, L99, V100, H109, A110, H111,L113, I122, C123, A127, V133, V134, L139, L153, p105 subunit M157, A160,C161, L170, L175, I196, A199, A200, V212, L214, F216, A218, A238, I239,A247, L250, V262, I268, L270, L271, I282, F284, I311, V312, F313, V329,V331, L333, F347, Y349, Y350, M808, L819, Y820, L823, L835, A836, F848,L858, M859, L872, A875, L876, A884, I888 375 C-X-C motif chemokine 3P19876 C45, I52, C69, V74, A76, L78, C85, L86, V93, I96, L101 376Complement receptor type 2 P20023 I47, I58, L63, C65, V96, Y108, V114,V130, C132 377 HLA class II P20036 M54, F55, F63, V65, F83, A87, A92,I94, L136, I137, C138, I140, F143, W152, F179, L182, V185, Y192, C194,V196, histocompatibility antigen, H198 DP alpha 1 chain 378 Myeloid cellsurface antigen P20138 V82 CD33 379 Kallikrein-2 (EC 3.4.21.35) P20151I25, C31, V40, A41, V53, L54, V55, V60, L61, A63, A64, C66, V73, L75,V90, V92, L121, L123, L124, L126, I132, V135, V136, C152, A154, F165,C173, V174, L176, C184, C198, A199, L217, C219, L223, I226, A241, V242,Y243, V246, I253 380 B-cell receptor CD22 P20273 W24, W35, C39, V40,I42, C44, L53, L76, F94, L95, C102, L117, L119, W128, M129, L134, V136,I145, C161, C167, Y170, I172, W176, V198, L204, F206, W210, C219, L229,L236, V238, V255, C265, W279, L294, L296, Y307, C309, L325, V327, Y329,V349, C353, A357, W366, Y394, C396, L413, V415, V422, I426, I432, V438,L440, C442, V451, W456, L470, I472, V475, W477, C484, A486, C491, L499,V501, Y503, A504, V508, V510, L527, C529, V539, W543, L556, I561, Y569,C571, I577, V589, Y591, L596, V598, V606, L614, C616, A620, Y627, W629,F630, L644, L646, Y657, C659, V677, Y678, Y679, I684 381 Integrinalpha-L P20701 F45, I57, V58, L70, C73, L109, A110, C111, C119, C129,Y130, V155, L157, V158, F159, L160, F161, L167, I175, F178, M179, V182,M183, L186, Y191, F193, A194, A195, V196, F198, F206, F208, Y211, A236,I237, V240, V244, V258, L259, I260, I261, I262, I273, A276, I279, Y282,I283, I284, I286, F290, L299, F302, A303, F310, F317, L320, L323, F324,L327, V364, V365, A367, A370, A374, F377, L378, L404, L411, L420, A421,V433, L434, L435, V467, L477, L478, L479, I480, A482, V494, L510, F521,L528, I531, V539, A540, V541, A543, A550, Y552, I553, F554, L561, I569,I578, F581, A597, A600, A603, M607, I608 382 Integrin alpha-X P20702F30, F37, V49, V50, V51, A53, L66, C69, A87, M90, L92, L105, L106, A107,C108, C126, F127, I152, V153, F154, L155, I156, M170, F173, V174, V177,F188, L190, M191, F193, F201, F203, F206, L216, A229, A231, I232, V235,L239, I253, L254, I255, V256, I257, V272, I273, A276, I282, A285, I286,V288, A291, F292, L301, I304, A305, F314, V316, F319, L322, L329, I333,F334, A352, V366, L367, A369, A379, I391, M400, L405, A412, L420, V421,L422, A424, A433, V434, I435, F436, V465, V467, L475, V476, L477, I478,A480, V492, V494, C495, L510, F521, L528, V531, V539, V540, I541, A543,A552, V553, Y554, L555, F556, I572, A573, L581, F584, L602, A603, V604,A606, V610, L613, V618, L619, I632, V650, I658, L671, V675, L681, A690,F692, L700, F715, L717, L719, I730, L732, L734, L749, L765, L793, V795,L801, A803, V805, V807, I819, F821, H823, C863, A880, F882, A888, L894,L896, A898, V924, A951, H953, Y955, V957, L965, V967, I969, F971, V973,L977, V982, W983, I1014, L1020, A1025, C1027, C1032, F1037, V1039,L1043, F1045, L1047, L1051, W1055, I1059, V1064, V1066, A1070, I1072,L1097 383 B-cell lymphoma 3 protein P20749 L139, V143, V151, F158, L176,H177, A179, V180, V188, L191, A208, H210, A212, C213, C220, L221, A223,L224, A245, L246, H247, A249, V250, V258, L260, L261, L280, I281, A283,V284, M291, V292, L294, L295, A312, L313, A316, V325, L328, V354 384Calpain-3 (EC 3.4.22.54) P20807 L138, L145, L189, F200, A210, L212,Y216, A218, F239, A335, V363, F404, F658, A662, I668, L673, L677, V681,C697, M700, M704, L712, F717, L720, I724, F731, I742, M747, A750, V751,A754, Y763, I777, F779, F782, I783, C785, F786, L815 385 Collagenalpha-1 P20849 L59, V65, A86, F113, L114, F117, M119, W128, I130, W131,I133, I144, I146, V153, F155, F169, I183, M184, I185, V187, A192, L194,A218, V219, V231, L235, M238, I240 386 Nebulin P20929 A6617, F6631,I6637 387 N(4)-(beta-N- P20933 I91, L105, I108, A111, I112, V114, A115,V118, A132, A136, A243, A253, A254, A256, L263, A272, V273, A285, C286,acetylglucosaminyl)-L- I290, I293, F300, A303, V304, C306, C317asparaginase (EC 3.5.1.26) 388 Filamin-A P21333 F49, C53, L57, I64, L67,L71, L77, I78, L80, L81, V107, V109, A110, L111, F113, L114, I129, I137,L138, L140, I141, L144, I145, I150, L172, I176, L180, I185, F188, W192,A197, L198, A200, L201, V202, A206, C210, A225, A228, M229, A232, L236,I238, V241, I242, I247, V257, M258, Y260, L261, F264, A284, A302, V306,A311, V318, V344, H354, V356, V358, F360, I365, V372, V495, A501, V505,A510, V519, F540, Y542, Y550, V552, I554, I561, V568, A595, F597, V598,V599, V633, Y635, Y643, A644, V647, I654, A661, V675, V697, H743, A745,V747, V761, V1070, F1088, I1090, A1095, V1124, Y1126, Y1134, I1136,I1138, I1145, A1152, V1154, V1163, C1165, F1181, V1183, A1188, I1197,I1219, Y1221, Y1229, V1231, I1233, Y1235, L1247, V1258, V1270, F1278,V1280, V1297, Y1317, V1319, Y1321, H1329, V1331, V1333, V1347, V1358,F1376, V1378, A1383, V1412, Y1414, Y1422, L1424, V1426, V1433, V1440,V1451, V1463, V1473, A1478, V1487, V1509, I1521, V1523, Y1525, V1530,V1537, V1539, V1548, V1560, A1562, F1568, I1570, A1572, A1575, I1584,V1606, Y1608, Y1616, I1618, I1620, Y1622, I1627, V1634, A1636, A1642,C1645, I1672, V1674, A1679, V1684, V1688, I1710, A1714, Y1720, I1722,V1724, V1731, V1738, A1740, F1791, I1795, I1799, V1808, V1828, V1830,H1840, M1842, I1844, I1851, L1856, F1858, V1860, V1868, A1870, L1875,F1886, V1888, I1902, V1922, Y1924, Y1932, I1934, V1936, V1943, F1948,A1950, V1952, V1987, I2009, F2011, H2019, V2021, V2023, I2039, A2047,V2050, L2057, F2068, I2070, A2075, L2080, L2082, I2084, V2104, Y2106,Y2114, I2116, I2118, F2120, V2125, V2132, V2134, A2176, V2178, Y2198,I2200, H2210, V2212, V2214, V2230, A2238, V2241, A2257, F2259, I2261,A2268, I2273, V2275, V2295, Y2297, V2299, Y2305, V2307, V2309, F2311,I2316, V2323, V2325, A2326, A2332, L2335, L2345, V2355, L2357, A2360,I2364, V2368, V2390, Y2400, I2402, V2404, F2406, I2418, V2432, L2439,F2450, V2452, A2457, V2485, Y2487, A2491, Y2495, I2497, I2499, Y2501,I2507, A2514, A2557, V2560, A2570, V2580, C2582, V2616, Y2618, L2620,L2628, V2630, W2632, I2637, V2644 389 Neurofibromin P21359 I1592, I1605,F1606, Y1607, V1609, F1613, L1623, V1642, A1670, Y1680, L1715, I1719,A1743, I1755, A1761, V1762, V1772, A1785, I1788, F1799, L1801, I1803,F1812, C1817, I1820, I1824 390 Phosphatidylcholine P21439 A64, M81,L109, M113, Y120, V127, A131, F137, A141, A142, I146, I149, F153, F154,A156, I157, L158, I162, L173, translocator ABCB4 L177, I181, I184, I188,A200, V208, L216, I220, A235, A252, A256, A259, A262, V266, A268, F269,Y279, L283, A286, A294, I303, A304, A310, A313, A315, F316, M334, V336,F337, I340, A350, A360, A364, I367, I371, I377, L394, V399, L412, L415,V419, V425, A426, L427, V428, C433, L441, I442, I453, I460, F463, V465,L468, I472, V475, L481, F482, I486, I490, I502, V506, A509, A511, I515,V526, I541, A542, I543, A544, A546, I553, L555, L556, A559, V571, A574,L575, A578, I585, I587, V594, I600, A601, F603, L617, Y624, V700, C717,A718, I735, I736, I753, I757, F758, L761, A779, L783, L787, A791, F792,M795, L796, L817, A821, V824, A827, A833, A840, L856, A896, A899, I900,I903, V906, F915, A934, C955, A960, L975, V976, F982, A1000, A1004,H1006, L1007, I1034, F1036, V1039, F1041, L1052, L1055, V1059, L1065,A1066, L1067, V1068, V1078, V1079, L1081, L1082, V1093, A1107, L1110,V1112, L1115, L1119, V1122, F1129, A1134, I1137, I1151, A1154, A1155,A1158, I1160, Y1171, V1175, A1191, I1192, A1193, L1196, L1204, L1205,V1220, A1223, C1233, I1234, I1236, I1243, I1249, V1250, V1251, L1266,Y1273 391 Tumor necrosis factor alpha- P21580 L10, A18, I21, I37, H38,H39, F40, M43, H44, L48, F51, I64, A67, L68, L77, L83, A94, L104, M105,H106, A107, Y111, induced protein 3 M112, W113, V115, L122, A125, L126,F138, A175, H195, I196, F197, V198, L199, C200, I202, L203, I207, I208,V209, V229, I232, Y233, L234, I248, V249, L250, V258, L260, V261, A272,V273, V288, H289, F290, L291, L302, L307, V314, I325, A327, A328, L330,I339, L341, Y345, V349, C404, C624, C779 392 Kit ligand (Mast cellgrowth P21583 V40, L43, L55, I70, M73, V74, L77, L81, I100, I101, L104,I107, V108, F140, F141, F144 factor) 393 Ephrin type-A receptor 1 P21709L81, A92, V95, H96, V97, L99, F101, V103, F122, L124, V148, L181, L183,A184, F185, A190, V192, L194, V197, V199 394 Fibroblast growth factor 7P21781 L69, C71, L77, I79, V85, M98, I100, V108, I110, L119, A120, M121,C137, F139, Y151, V165, A166, L167, A186, F188 395 Fibroblast growthfactor P21802 M162, V169, V175, F177, C179, A181, F198, L216, M218,V221, Y229, C231, V233, Y244, L246, F276, C278, W290, receptor 2 I324,C342, A344, A355, L357 396 Ryanodine receptor 1 P21817 L13, V19, V20,L21, C23, A25, L34, C35, L36, A37, A38, I63, C64, F66, L68, L77, L100,Y102, A105, I106, L108, H110, L117, A131, V134, L136, C145, W147, M149,V162, I168, L170, L179, V190, A192, W199, M201, V213, L219, L221, H223,C229, L230, I232, V244, Y246, V251, A255, L258, W259, L261, L273, L279,V281, H283, V284, Y289, L290, A291, V299, V300, A306, F313, F315, I338,C345, V347, L356, A375, L387, L389, A399, A400, M402, I403, Y410, F413,L435, V440, L444, L447, I448, F451, L470, L476, F477, M482, V486, C489,I490, L493, F502, A506, I517, V518, L521, L524, L528, W685, A686, V706,C745, I754, V779, V780, A874, F909, V984, A988, H992, L1038, V1042,A1093, V1101, W1103, A1104, L1114, A1120, V1122, F1123, V1148, C1150,I1152, I1159, F1161, I1181, V1190, A1449, W1451, V1452, L1465, V1471,V1473, M1475, I1515, M1526, F1528, A1550, F2754, A2759, Y2761, H2763,A2767, L2813, A2815, M2816, L2862, M2874, L2878, A2879, A2923, L2926,L2927, L2930 397 Receptor tyrosine-protein P21860 L52, Y53, C56, V58,V59, L63, I65, L77, I80, V83, V87, L88, V89, A90, F94, L97, L99, L102,V104, V105, A116, I117, kinase erbB-3 (EC 2.7.10.1) F118, V119, L121,A130, L131, L134, L136, L139, I142, V147, I149, L155, M158, I161, I166,V167, C190, C194, W195, C231, A232, A245, C255, C259, V295, V296, C331,V343, I348, F351, C354, I357, L361, F363, I376, L384, F387, V390, I393,L397, I399, F409, V411, F412, L415, I418, F428, L430, I432, V438, L441,F443, L446, I449, I454, I456, L462, C463, H465, V473, L474, C493, C504,C509, W510, C529, C533, C552 398 Succinate dehydrogenase P21912 F42,I44, V63, V72, A75, L76, I79, L87, C101, M103, L111, A112, I127, F146,L183, A190, C191, Y199, Y206, A210, [ubiquinone] iron-sulfur V211, L212,A215, L234, L240, A262, I263, I266 subunit, mitochondrial (EC 1.3.5.1)399 Tenascin-X P22105 C435, C466, L3669, L3671, A3679, F3683, L3685,A3716, L3718, L3729, L3731, A3859, L3861, Y3873, V3875, V3877, L3898,A3909, V3911, A3947, L3949, Y3961, L3963, L3977, L3986, Y3995, A3997,L3999, A4001 400 Cadherin-3 P22223 V116, L131, I141, V157, F158, L167,L169, L173, L183, A187, I201, I203, V224, V237, A254, M269, I279, V281,Y294, L296, I298, A300, A312, A314, V316, I318, L349, L390, L396, L406,V408, V410, A425, I427, V429, Y462, V495, L501, Y514, V516, V518, A520,L534, L536, I553, L565, V602, L604, V617, L619, L621, I633, A635 401Interleukin-10 P22301 L41, L44, A47, V51, F55, L66, L70, A82, L83, M86,Y90, V94, A98, V109, L112, L116, C126, L130, V139, A157, M158, F161,F164, I165, I168 402 C-C motif chemokine 1 P22362 I47, L62, F64, A74,V81 403 Ectonucleotide P22413 C164, C166, C170, A392, I507, I632, F638,L826 pyrophosphatase/phosphodi- esterase family member 1 404 Potassiumvoltage-gated P22460 I124, I126, L138, L146, F165, F172, I175, Y179,V191, F196, I200, Y203, I260, V445, A451, V452, A455, A470, A474,channel subfamily A C500 member 5 405 Protein-glutamine gamma- P22735V709, I711, L721, V724, F726, L728, I744 glutamyltransferase K (EC2.3.2.13) 406 Carbonic anhydrase 4 (EC P22748 Y25, I54, I56, Y75, W81,V83, V90, M92, L94, I100, Y109, A111, L114, L116, W118, H128, M137,M139, H140, I141, 4.2.1.1) H143, A164, L166, A167, F168, L169, V170,F180, L187, I190, Y217, C229, V233, V237, F238, I242, L244, F252, L256,M266 407 Peptidyl-prolyl cis-trans P23284 V42, V44, V46, Y47, F48, L50,I52, V60, I61, F62, L64, F65, V69, V73, F76, A78, L79, A80, F86, Y88,F93, V96, I97, isomerase B M101, I102, I118, F123, L130, H132, W137,V138, M140, F152, F153, I154, V167, V168, F169, V172, V178, V179, V182,L194, V197, I198, I199, I205 408 Glycine receptor subunit P23415 V65,V67, C69, I71, I73, Y86, V88, I90, L92, W96, L101, L111, L146, I148,V154, I160, L162, L164, C166, L170, F173, alpha-1 C180, M182, L184,L194, F196, C237, I238, A240, F242, L244 409 Receptor-type tyrosine-P23468 A41, F43, C45, W57, F69, V81, L82, I84, L87, Y96, C98, A100,L113, V115, A143, M145, C147, A148, A149, W159, protein phosphatasedelta L192, I194, Y205, C207, A209, A221, L223, I255, C257, A259, V267,W269, V294, C302, A304, A315, I317, I339, L341, I356, V373, V380, F391,V393, V394, A395, I434, V436, V453, V463, I479, V490, V492, A494, I532,L534, Y547, L549, I564, L575, F583, L585, A586, A587, I626, V628, I647,A651, L674, I685, V687, A689, L937, L956, L981, V992, V994, A996 410Tumor necrosis factor ligand P23510 V64, F66, M86, V93, I95, C97, Y101,I103, L105, V113, I115, L117, V135, V149, L151, L170, L172 superfamilymember 4 411 Brain-derived neurotrophic P23560 C141, A150, V164, V166,V170, C196, A217, I226, I231, I233 factor 412 Follicle-stimulatinghormone P23945 F30, C32, V37, A48, L51, F53, L58, I61, F66, F69, L72,I75, I77, L83, I86, V90, F91, L94, L97, I100, I102, A105, L108, receptorL109, A115, F116, L119, L122, L125, I127, I132, L135, V138, I141, V147,L149, I151, I157, I160, F165, L168, V173, L175, L177, I182, A189, F190,L195, L198, L200, L206, V213, L223, I225, I230, L238, L241, L244, A246,L261, A267 413 Sodium-dependent P23975 L95, L109, A145, I156, L238,F272, L284, I291, A305, I309, L319, V325, Y367, V379, L386, V387, F388,I389, L390, noradrenaline transporter Y391, A394, A405, I428, F459,I466, L469, L472, A477, L486, I490, F495, F540, I549, A554, W556, V569414 Protein kinase C eta type P24723 V360, M370, L371, A372, V383, V390,I406, L407, A410, F415, L416, L429, F430, F431, V432, L441, A456, Y459,(EC 2.7.11.13) A460, A461, I463, I464, A466, L467, L470, I475, Y477,V485, L487, C493, L495, F498, W537, M540, L543, L544, M547, A581, I584,L585, F588, I608, F613, F614, V641, F644, F671, F674 415Deoxyribonuclease-1 (EC P24855 I25, A26, A27, F28, I30, F33, M38, V44,I47, V48, I50, L51, Y54, I56, A57, L58, V59, V62, A69, V70, L73, L77,Y102, 3.1.21.1) L103, F104, V105, V111, F131, I137, V138, F140, V147,F150, A151, I152, V153, L155, A157, A162, I166, L169, V172, V176, V185,M186, L187, M188, F191, A193, I206, L208, I218, C231, A232, I236, V237,V238, A239, L243, A246, F257, A268, I271, V277, V279, L281 416 C-X-Cchemokine receptor P25024 L37, C110, C187, V190 type 1 417 C-X-Cchemokine receptor P25025 L155 type 2 418 Adenomatous polyposis coliP25054 L137, L204, I224, C344, L356, A383, A386, L387, I391, V406, L407,L410, I413, Y416, C417, C420, I446, V450, L453, protein A465, M466,L469, L472, A474, I475, A476, L478, L479, V481, L497, A501, A504, L505,L508, L519, C520, C525, M526, L529, L540, I544, A545, V547, L548, L551,L563, V569, L572, M573, C575, A576, V588, L589, A591, L592, L595, I606,A612, L613, L616, I631, I638, L639, V642, I646, L656, C661, L665, I676,A680, C681, L684, L687, A703, L707, I718, A725, L729 419 Myelin proteinP0 P25189 L48, C50, F64, W66, F80, F95, I112, I114, F125, C127, L144 420Tumor necrosis factor P25445 C63, C73, C85, C119 receptor superfamilymember 6 421 Integrin beta-7 P26010 C54, I55, C61, W63, C64, L86, L123,A124, V128, V130, L132, V142, F144, V152, L154, Y155, Y156, L157, M158,L160, M164, I191, F193, F196, V197, F204, V205, C216, F229, F242, V246,V251, A264, I265, L266, A268, A269, C271, I275, L283, L284, V285, F286,Y327, L337, A340, I345, A347, V348, Y356, A367, V378, A385, L395, Y408,C428, V431, V437, F439, V441, L443, A445, L455, L457, A459, L466, V468,L470 422 Hemagglutinin [Cleaved P26136 I29, C30, L31, A35, V42, V52,L58, V59, L67, C68, L74, C80, L82, I83, A86, L87, C92, L95, V102, F103,I104, V110, into: Hemagglutinin HA1 C113, Y114, F116, Y121, L124, L128,A129, L134, F141, A154, C155, F163, F164, L167, L170, I181, Y195, W197,chain; Hemagglutinin HA2 V199, H200, H201, Y212, V219, V221, I247, I249,Y250, L253, V254, I260, F262, L268, I269, A270, Y275, I292,chain]/strain C299, L300, I306, V327, L334, A335, A352, W361, Y369,A391, A443, L465, L473, C484, F485, I487, H489, C491,A/Mallard/Astrakhan/263/ C495, I496, I499, A513 1982 H14N5 (Influenza Avirus (strain A/Mallard/Gurjev/263/1982 H14N5)) 423 Hepatocyte growthfactor- P26927 C157, C169, Y199, W215, C240, W250, C251, Y252, C263,L265, C391, W394, H400, L414, C419, C431, C443, V484, like protein W494,V496, L498, L511, I517, L518, A520, V536, L538, V555, L569, V570, L571,L572, V584, C602, I604, A605, L624, C632, M645, C646, L665, A666, C667,L675, I678, I679, V697, I704 424 Serum P27169 L28, I48, A63, F64, I65,I85, M88, L129, L130, V131, V132, V141, L143, F144, L153, I159, L167,I170, F178, Y179, paraoxonase/arylesterase 1 G180, V205, F220, A223,I226, V235, I237, A238, I245, V247, L267, V268, L280, V282, C284, H285,V304, I307, A322, L328, V333, A334, L341, L342, I343, A350, L351, C353425 Dipeptidyl peptidase 4 (EC P27487 Y43, Y68, L69, A81, L90, I114,L116, A130, Y132, I134, L142, L164, A165, V167, I172, V174, I198, W201,V202, Y203, 3.4.14.5) V207, A213, L223, A224, Y225, A226, F228, I236,Y238, Y241, A259, A261, F268, V270, V271, I287, M293, Y299, L300, C301,V303, I311, L313, W315, V324, M325, I327, C328, C339, L340, I346, W353,V354, F371, H383, I384, C385, I389, V404, L415, Y416, Y417, I418, L431,I434, V442, L445, C447, C454, Y468, L470, C472, L482, L500, V507, L514,L519, M528, L530, L542, L543, L544, V546, A548, C551, A555, L567, A568,I573, I574, V575, A576, F578, M591, A593, I594, L598, V603, I607, A609,A610, F613, V619, I624, A625, I626, Y631, Y634, V635, M638, V639, L640,C649, I651, A652, V653, A654, V656, W659, Y661, Y662, V665, Y666, Y670,M671, Y683, V688, A692, F695, Y700, L701, L702, I703, H704, V711, I719,L723, V724, V726, F730, Y735, H740, I742, I751, M755, F758, I759, C762,F763 426 Genome polyprotein P27909 L29, M48, M126, V128, C148, C167,C180, C182, V189, Y191, A251, A255, M281, C283, V301, V303, V304, L305,[Cleaved into: Capsid C310, V311, M314, A315, L321, I323, L325, V330,L339, C340, I341, A360, C385, L394, C396, A397, F399, L405, proteinC/strain Brazil/97- V410, L415, Y417, V419, V421, I444, I453, L455,L461, L463, C465, L471, V477, L478, L479, M481, V488, F493, L517,11/1997 (DENV-1) V518, L544, H562, L563, C565, L567, M569, L572, C582,F586, V592, V600, V602, V604, Y606, C613, I615, I632, V638, I647, I658,V660, W671, I963, I993, L1396, L1398, I1497, Y1498, I1500, V1513, V1515,F1516, V1520, F1521, H1522, M1524, L1533, M1534, V1547, L1551, I1552,Y1554, W1558, F1560, V1570, V1572, I1573, A1574, V1575, V1584, F1591,A1600, I1601, I1614, V1615, V1622, L1624, Y1625, V1630, Y1636, V1637,A1643, L1680, I1683, V1684, A1687, L1695, I1696, L1697, A1698, V1703,A1704, M1707, A1708, L1711, V1733, L1735, M1736, H1738, F1741, Y1754,M1756, I1757, I1758, M1759, A1762, I1770, A1771, A1772, I1776, A1785,A1786, A1787, I1788, F1789, M1790, I1827, V1835, W1836, F1837, V1838,I1847, A1848, C1850, L1851, I1859, L1861, F1866, W1878, Y1880, V1881,V1882, A1891, V1898, I1899, V1917, V1925, A1928, A1930, A1931, I1937,Y1948, V1949, L1955, A1962, A1967, L1970, L1971, I1974, L1984, F2009,V2010, L2012, L2018, W2021, L2022, V2026, A2027, W2038, C2039, V2048,I2057, L2067, A2074, F2086, F2089, A2090, W2506, Y2521, I2526, V2529,L2538, A2547, V2548, A2553, L2555, F2558, V2559, V2564, V2570, I2571,L2573, C2575, C2584, A2585, V2590, V2593, Y2596, V2625, C2633, L2636,L2637, C2638, I2649, L2655, V2657, L2658, V2661, W2664, L2665, C2671,I2672, I2674, L2675, Y2678, V2682, L2686, M2689, M2696, L2697, H2708,M2710, Y2711, W2712, V2713, I2720, V2724, M2730, L2731, I2769, I2776,V2817, L2820, W2824, I2865, M2866, A2870, L2873, V2904, A2914, A2917,F2923, C2939, C2942, V2943, Y2944, M2969, L2971, A2973, L2976, A2980,F2983, M2984, W2989, F2990, V2999, L3007, Y3009, L3011, I3014, I3017,M3022, I3034, A3057, I3060, Y3065, V3069, V3070, V3072, V3081, V3084,I3085, L3101, F3104, M3107, V3109, L3111, I3112, M3115, L3126, V3135,L3139, L3147, M3150, A3151, I3152, V3158, V3159, F3166, A3169, L3170,A3172, L3173, M3176, V3198, F3200, F3205, I3216, V3217, V3218, C3220,V3227, A3230, A3236, A3244, A3251, W3254, L3256, F3259, H3260, L3264,A3267, A3268, A3270, I3271, A3274, V3275, V3277, H3290, L3302, W3305,V3308, W3309, W3315, V3328, L3331, A3352, I3355, I3359, L3365, L3372,M3375, M3378 427 Interleukin-1 receptor type 2 P27930 V46, L48, W69,A92, L93, L95, A98, C108, I121, L150, W169, L192, V194, Y205, C207,I220, I224, C258, V260, L262, A276, I281, V328 428 Genome polyproteinP27958 V194, V203, C207, C226, C229, V230, C238, W239, V240, L258, I262,L265, A269, C272, L275, C281, L286, F291, [Cleaved into: Core proteinW353, V355, A426, L427, W437, F442, C459, F465, C486, C494, A499, V502,C503, V506, C508, F509, F537, L539, p21/genotype 1a (isolate H) W549,C552, W554, C564, A566, C569, C581, C585, F586, A592, Y594, C597, I603,C607, M608, V609, Y611, V629, (HCV) M631, A642, A643, C644, C652, L665,V674, A684, I690, L692, V699, Y701, V720, L724, L725, L754, C922, V949,L964, A1004, I1061, L1070, A1071, C1073, I1074, V1077, C1078, W1079,V1081, A1085, V1097, L1108, V1109, L1120, L1130, L1132, I1140, V1142,I1158, L1161, L1169, C1171, A1176, V1177, L1179, F1180, A1190, A1192,V1193, F1195, I1196, V1198, L1201, L1228, V1251, L1252, V1253, L1254,M1268, I1291, Y1293, Y1296, A1301, I1312, I1314, C1315, C1318, I1326,I1329, V1332, A1336, L1343, V1344, V1345, L1346, A1347, I1362, I1373,F1375, I1380, V1384, I1385, L1391, I1392, F1393, C1394, C1400, L1403,L1407, I1412, V1432, V1433, V1434, V1435, L1440, F1444, F1448, V1451,I1452, F1470, A1481, Y1499, L1517, C1518, C1520, Y1521, A1526, Y1528,L1539, Y1542, L1555, F1557, W1558, V1561, L1565, I1568, F1572, L1586,V1587, A1588, A1591, C1594, A1599, L1611, H1619, L1624, L1625, L1628,I1641, I1645, V2128, L2441, L2450, L2451, V2457, Y2458, A2465, Y2484,V2487, V2491, A2493, A2494, A2495, V2498, A2500, A2508, C2509, Y2523,A2525, V2528, A2532, A2535, I2539, L2546, L2547, I2558, C2566, A2577,L2579, V2581, L2585, V2587, V2589, C2590, A2594, L2595, V2598, V2599,L2602, A2605, V2606, Y2611, V2621, L2624, A2627, M2635, L2637, Y2639,V2648, I2653, I2659, Y2660, C2662, C2663, A2669, A2672, I2673, L2676,L2680, Y2681, L2686, C2694, C2699, A2701, V2704, L2705, C2709, L2713,A2719, A2721, A2722, C2723, A2726, L2728, M2733, L2734, V2735, L2740,V2741, V2742, I2743, C2744, A2754, L2756, F2759, A2762, M2763, Y2766,A2768, I2783, V2790, A2793, Y2802, L2804, L2812, A2813, A2815, A2816,L2829, I2832, I2833, A2836, L2839, W2840, A2841, I2844, L2845, M2846,H2848, F2849, F2850, L2859, A2862, C2865, I2867, A2870, C2871, Y2872,I2874, L2877, L2879, I2882, I2883, L2886, A2891, F2892, V2905, A2906,C2908, L2909, L2912, V2914, A2919, W2920, A2924, V2927, L2931, L2932,A2938, A2939, C2941, L2945, F2946, A2949, A2961, A2962, F2971, A2973,Y2975, I2980 429 Proteasome subunit beta P28062 L76, A77, F78, F80, V84,I85, A86, A87, V88, A92, A94, V106, I107, L113, L114, M117, C124, L131,C135, L137, I146, type-8 (EC 3.4.25.1) V148, A150, A151, L155, M159,M169, M172, I173, C174, L183, V186, A207, M211, A224, L227, A231, I232,A233, A235, V245, V246, M248, Y249, H250, M251 430 HLA class II P28068L51, M61, A73, L90, C97, V117, V119, M132, L133, A134, C135, V137, F140,W149, C192, V194 histocompatibility antigen, DM beta chain 431Gamma-aminobutyric acid P28472 V63, M65, I67, I69, Y82, L84, M86, W92,L97, I141, V149, A159, L165, C175, L177, I179, I189, A199, L233, L235,receptor subunit beta-3 F237 432 Mitogen-activated protein P28482 A9,V14, F19, V21, Y25, I31, A35, Y36, M38, C40, A42, V49, V51, A52, I53,I56, C65, L69, I72, I74, L75, I83, I84, I86, kinase 1 I89, I95, M98,V101, Y102, I103, V104, L112, L115, L116, L121, H125, I126, C127, F129,L130, I133, L134, L137, I140, H141, A143, V145, L146, H147, L150, L155,L156, L157, L163, I165, F168, L170, A171, L184, A189, W192, Y193, A195,I198, M199, L200, Y205, I209, I211, W212, V214, C216, I217, L218, A219,M221, L222, I227, F228, L234, L237, I240, L241, L244, L252, I255, A260,L264, L267, F279, A286, L287, L289, L290, M293, L294, A307, L308, L313,F329, M333, L335, L338, L343, I347 433 Granulins (Proepithelin) P28799C133, C157, C215, C239, C290, C314, C372, C396 (PEPI) [Cleaved into:Acrogranin (Glycoprotein of 88 Kda) (GP88) (Glycoprotein 88)(Progranulin); Paragranulin; Granulin-1 (Granulin G); Granulin-2(Granulin F); Granulin-3 (Granulin B); Granulin-4 (Granulin A);Granulin-5 (Granulin C); Granulin-6 (Granulin D); Granulin-7 (GranulinE)] 434 ADP-ribosyl cyclase/cyclic P28907 F59, V63, C67, Y70, M77, V85,F89, A92, F93, I101, Y106, L109, M110, C119, I122, L123, L124, A132,F135, L145, ADP-ribose hydrolase 1 (EC L149, L150, L153, A154, W159,C160, V187, F188, V192, A197, A199, A200, V204, V206, M207, L208, I215,F216, 3.2.2.6) F222, V225, V227, L230, V235, L238, A240, V242, L253,I259, L262, I266 435 Tumor necrosis factor P28908 C44, C45, C48, C58,C65, C69, Y74, C81, A83, C84, V85, C87, L92, V93, C98, V105, C106, C108,F113, C114, C122, receptor superfamily A123, C125, C131, I136, V137,C233, C240, C244, Y249, L250, C256, C259, V260, C262, L267, V268, C273,W275, member 8 C281, C283, C289, C297, A298, C300, C306, V311 436 Gapjunction beta-2 protein P29033 W44, F51, C60, C64, H73, C169, A171, C180437 Neuroendocrine convertase P29120 C319, A393, V411, A511, L525 1 438Amyloid beta A4 protein P29216 C49, C53 439 Ephrin type-A receptor 3P29320 L33, Y68, V70, L82, V87, A92, I95, Y96, V97, L99, F101, L103,V112, F120, L122, I146, M155, V171, F179, Y180, L181, (EC 2.7.10.1)A182, F183, A188, V190, A191, L192, V195, V197, A436 440 Ephrin type-Breceptor 2 P29323 W43, V61, W72, L73, I78, A83, I86, V88, M90, F92, V94,V103, F111, L113, I141, V150, I159, F166, V169, F174, Y175, (EC2.7.10.1) L176, A177, F178, L187, V190, V192, A435 441 Collagen alpha-5P29400 I1464, L1490, Y1491, L1503, Y1537, W1538, L1539, I1561, C1564,A1565, V1566, C1567, A1569, F1599, H1602, C1620, F1629, I1630, C1632,C1638, C1678, V1680, C1681, M1682 442 Interleukin-12 subunit alphaP29459 V48, M51, A55, I105, C123, L131, M141, M159, I163, C196, L199,I209 443 Interleukin-12 subunit beta P29460 V30, V32, V33, V46, I58,W60, V79, A85, C90, L102, L104, I116, A133, F140, C142, W144, V191,C193, I208, V210, V212, A214, Y220, Y223, I229, I233, V252, V254, L271,F273, C274, V275, V277, A304, I306, V308, A310 444 Protein PML P29590C57, C66, L73, H74, L76, C129, C140, C148 445 Non-receptor tyrosine-P29597 L28, V30, A53, V56, I60, A61, V64, L73, L76, A81, L91, L101,F103, F109, Y151, L152, F153, F160, A165, L184, M186, protein kinaseTYK2 (EC A187, L191, H193, C214, I215, F219, Y259, L260, L263, A267,V277, L280, L283, V316, V318, I324, C378, F380, 2.7.10.2) V393, I395,C402, L403, L405, L407, A413, F416, V417, L419, V420, Y423, L426, V438,H452, Y471, L472, L483, L485, V487, I507, V526, L529, I563, V639, L641,L644, F655, A659, V676, C677, I684, M685, V686, L695, L699, V714, A715,L718, A719, A721, L722, L725, V735, I740, L742, I755, L757, V762, V773,I776, A780, W798, F800, A802, L804, L805, I807, C838, L841, L844, C848,F859, I862, L866, L913, V927, V929, A934, W944, I948, L951, H958, I959,I960, C966, L974, L976, V977, L986, L990, L1000, L1001, F1003, A1004,I1007, C1008, M1011, L1014, I1020, H1021, L1024, A1025, A1026, V1029,L1031, V1037, I1039, F1042, L1044, A1045, A1069, C1072, F1078, V1084,F1087, V1089, L1091, Y1092, L1094, L1124, L1127, L1128, L1134, C1140,V1144, M1148, C1151, W1152, L1165, L1169 446 CD40 ligand P29965 A124,V126, L138, V153, L161, V163, Y169, I171, A173, V175, F177, F189, A191,L193, L231, A235, V237, V239, V241, F256, L258 447 Peroxiredoxin-5,P30044 V67, V76, L78, F82, V88, L89, F90, V92, F96, C100, H104, L105,F108, A112, L115, A117, V123, A124, C125, L126, mitochondrial (EC V128,A131, W137, A140, A143, L150, A151, F157, L178, F181, M183, V184, V185,V190, A207, I210 1.11.1.15) 448 T-cell differentiation antigen P30203V58, V60, A78, A79, A81, V82, C83, A126, A151, V153, A171, V174, M176,V185, C186, A195, V197, V198, C199, CD6 A255, A257, V278, V280, F282,V289, C290, A299, V301, L302, C303, C308, M326, Y328, L337, A355, V358,C360 449 Lens fiber major intrinsic P30301 A12, A15, A19, Y23, V24, L28,L32, V44, A45, F48, A51, V67, A70, V71, A74, A86, Y89, A97, A101, V112,L116, V127, protein A130, V142, I145, F146, A161, V164, L168, H172,A181, M183, A186, A190, A192, V203, Y204, I209 450 HLA class I P30460M29, Y31, A35, F46, V52, F57, V58, F60, A73, W75, I76, Y83, F91, L102,L105, L119, M122, C125, V127, Y140, Y142, histocompatibility antigen,Y147, I148, L150, L154, W157, A163, A164, V176, A177, L184, C188, V189,L192, Y195, L196, L203, V213, A223, B-8 alpha chain L225, C227, A229,F232, Y233, L239, W241, A269, A270, V271, V272, V273, Y281, C283, V285,H287 451 Tyrosine-protein kinase P30530 L54, C56, L58, V98, L102, C117,V119, V133, C160, W173, F203, C205, A207, A219, I221 receptor UFO (EC2.7.10.1) 452 Type-1 angiotensin II P30556 I27, C101 receptor 453Fibroblast growth factor 9 P31371 L66, C68, L74, I76, I94, L95, V105,I107, L116, M118, C134, F136, Y148, V164, A165, L166, F184, F187, V197,L200 454 Cytokine receptor common P31785 C62, V64, M70, C72, W74, L85,L87, C102, L106, C115, L117, L124, F128, V129, V130, L132, L146, L148,V152, subunit gamma L162, L165, L170, L172, W174, L183, H185, V187,F221, V223, F227, A234 455 Low affinity P31994 A50, L62, V67, L69, W84,A103, Y111, C113, L126, L129, L133, V134, L135, L140, F142, I148, L150,C152, L160, immunoglobulin gamma Fc V163, F165, F166, F181, A186, Y194,C196, I212, V214 region receptor II-b 456 Low affinity P31995 A50, L62,V67, L69, W84, A103, Y111, C113, L126, L129, L133, V134, L135, L140,F142, I148, L150, C152, L160, immunoglobulin gamma Fc V163, F165, F166,F181, A186, Y194, C196, I212, V214 region receptor II-c 457Carcinoembryonic antigen- P31997 L36, A45, V51, L52, L53, V55, Y65, W67,I79, I80, A105, L107, M109, V112, Y120, L122, V124, F138 related celladhesion molecule 8 458 Neuronal acetylcholine P32297 A139, L140, A153,I187, L189 receptor subunit alpha-3 459 4-hydroxyphenylpyruvate P32754V22, F24, A29, A33, M40, F42, V61, I62, I67, V68, F69, L71, I96, F98,C103, V107, A110, V131, A134, L136, H144, dioxygenase (EC 1.13.11.27)L146, V147, C176, I184, V185, Y200, V217, L224, V228, V229, A230, I236,M238, I240, I252, I267, A268, L269, I274, A277, I278, L281, Y296, L317,I322, Y331, L332, L333, I335, L346, F347, L348, V350, I351, F368 460T-lymphocyte activation P33681 A46, L48, C50, I64, W66, V73, L74, L99,I101, I103, Y114, C116, V118, I160, C162, W175, V200, L204, F214, C216,antigen CD80 I218 461 Surface antigen S/isolate P33795 F36, A66, L83,I210, V238 Human/India/Ind3/1967 (VARV) (Smallpox virus) 462N-acetylgalactosamine-6- P34059 I33, L34, L35, L36, L37, M38, M41, L46,M62, F69, F72, Y73, A75, A84, A85, L86, L87, L91, F97, A104, I113, I117,sulfatase (EC 3.1.6.4) L123, L124, L128, I137, V138, W141, L143, H154,W159, H166, V180, Y190, A203, Y209, A213, F216, I217, F226, F227, L228,Y229, W230, A231, V232, A234, Y240, A241, Y254, A257, V258, I261, I265,I268, L272, V283, F284, F285, A291, I294, C308, F314, M318, A322, L323,A324, W325, I342, F346, L350, L368, Y384, M391, A392, A393, A400, H401,V427, I441, F442, A464, I468, L486 463 Neurotrophin-4 P34130 V118, V120,A179, I193 464 Catenin alpha-1 P35221 A128, L141, L150, V157, I161,L164, L173, L187, A191, L198, M207, A208, L221, L229, L243, I244, L248,V252, I255, A258, A259, F285, L305, I312, A316, M319, I333, A339, V340,L344, L347, L348, M371, L378, L382, A385, V386, H389, V390, L395, L401,L404, A407, A408, V416, F423, A427, L430, V433, A434, A437, C438, V450,M452, L457, A459, L460, V464, A468, L471, A480, W491, V497, L498, A501,V502, F511, L512, V514, I519, C526, A529, L530, L538, A542, I545, A549,V552, V556, V572, L573, L579, V583, F587, A594, F611, A614, V618, I622,I625, F691, L698, I712, A716, M719, M723, M726, V742, A745, A746, I749,A752, M756, L759, I763, L776, L780, I783, L790, C793, A815, L818, I819,A821, A822, L825, M826, A828, V829, V833, A839, A896, A902 465 Cateninbeta-1 P35222 A149, I153, L160, V168, A171, A172, V175, I188, M194,V195, A197, I198, V199, M202, C213, A215, L218, L221, L228, I231, I237,A239, L240, V241, V251, L252, A255, I256, L259, L262, L263, A269, V273,L279, M282, L285, F293, L294, A295, C300, L301, L304, A305, I315, A317,L324, V325, I327, M328, L336, L337, V343, L344, L347, C350, I357, V358,A360, M363, A365, L366, L368, L370, L377, V378, C381, L382, L385, L388,A391, A392, M398, L401, L402, L405, V406, L408, L409, V417, C419, A420,A421, I423, L424, L427, V438, I444, L447, V448, V451, A454, I460, A464,I465, A467, L468, L471, A481, A484, V485, L491, V494, V495, L497, L498,L506, I507, A509, V511, L513, I514, L517, A518, L519, A522, A525, L527,A532, I533, L536, L539, L540, A543, V564, M566, I569, V570, C573, A576,L577, L580, A581, V584, I590, I596, L598, F599, V600, L602, L603, I610,V613, A614, A615, V617, L618, L621, A622, A627, A628, A630, I631, A633,A636, L640, L643, L644, V651, A652, A655, A656, V658, L659, L781 466Interleukin-13 P35225 L43, L46, I47, L50, C62, V67, M76, Y77, A79, A80,L81, L84, I93, L100, C104, V125, F128, V129, L132, L136 467Thrombospondin-2 P35442 I600, C619, A639, C707, C715, C720, C756, C779,C815, C838, C876, A882, C912, C932, C948, F959, V965, L967, L988, I998,A999, V1000, F1005, F1010, V1016, Y1024, A1025, F1027, V1028, F1029,Y1031, F1037, Y1038, V1039, M1041, A1057, L1065, V1067, V1068, L1078,A1081, L1082, W1083, V1092, L1114, H1116, I1123, V1125, Y1145, L1150,L1152, F1153, V1154, F1155, V1160, F1162, L1165, Y1167, C1169 468 D(3)dopamine receptor P35462 C103 (Dopamine D3 receptor) 469Alpha-L-iduronidase (EC P35475 V32, V34, W47, F52, A61, V65, L72, L74,A75, Y76, V77, A79, V88, W92, L93, L94, L96, V97, L114, Y117, L120,L121, 3.2.1.76) F130, L132, M133, A136, F140, F143, V149, W152, L155,V156, L159, A160, Y163, V172, W175, F177, W180, F198, Y201, Y202, A204,C205, L209, L216, L218, F225, L237, L238, Y258, I259, L261, I272, V279,I283, A300, A314, V316, Y318, A319, A320, M321, V322, V323, V325, I326,A327, H329, L333, A340, L346, A351, L353, F360, L365, A367, V371, L381,L382, V386, L387, A389, L393, A394, L396, L401, V418, L421, A422, A436,A437, V438, L439, I440, Y441, A442, A448, V456, L460, V472, L476, C481,F501, M504, A507, L530, L535, L537, V538, H539, V540, C541, V551, L564,V565, L566, V573, C577, L578, Y581, I583, L604, V614, Y618, V620, A622470 Fibrillin-1 [Cleaved into: P35555 C67, C80, C100, C134, C145, C853,C875, A882, I911, C1526, C1534, C1562, C1564, A1569, I1607, L1613,L1616, Asprosin] C2061, C2083, C2084, C2085, I2110, C2111, C2137, C2164,C2190, C2363, C2364, C2365, W2371, C2378 471 Myosin-9 P35579 V34, A44,A54, V56, L58, M86, L89, A95, V97, L98, L101, Y105, L109, I110, Y111,Y113, F117, C118, V119, V120, I121, I129, I134, V135, Y138, M146, H149,I150, Y151, I153, A157, M161, I170, L171, C172, A178, V187, I188, Y190,L191, A192, V194, A195, A214, I217, L218, A220, F221, A224, F235, F238,I239, I241, F243, V250, A252, Y257, L258, A264, F274, I276, F277, Y278,Y279, L280, L288, L292, L293, F302, L303, I310, F319, A325, M326, M329,L339, L340, V342, I343, V346, L347, L349, I352, F354, A363, A370, A371,V374, L377, L378, F385, I389, L390, A410, F412, A413, I414, A416, L417,A418, A420, Y422, M425, F426, L429, V430, I433, L437, I448, I450, L451,F456, F464, L467, C468, Y471, L479, F480, Y492, I497, F504, L508, C511,I512, L514, I515, I524, L525, L527, L528, F542, V546, F556, F568, C569,I570, I571, H572, V577, Y579, A581, W584, M589, I596, A597, L600, F607,V608, W612, V646, Y650, L654, L657, M658, L661, F668, V669, C671, I672,I673, V688, L689, L692, V697, I701, I703, F708, F714, F717, Y721, I729,A739, C740, M743, I744, V761, F762, F763, V767, L771, I783, F786, M809,M871 472 Alpha-actinin-2 P35609 F44, C48, L70, L75, L76, V100, L114,A119, I122, V123, I134, I138, A142, I143, I146, L157, C161, I173, W180,L184, L186, C187, A188, L189, I190, L203, I209, I212, A215, M216, A219,A231, V235, A244, I245, M246, Y248, V249, F252, Y253, A262, L289, A290,I297, L304, A315, M316, L348, L378, A381, L389, A403, F406, A410, H413,A417, L424, V437, H444, I461, A465, L468, V479, I486, L493, L504, M507,H518, F521, A525, M532, A535, I551, L565, I575, V582, I593, L607, V614,L625, A646, I649, I667, L678, H683, L695, V707, M717, I720, L727, I731,M798, A839, Y844, I845, L850, A859, I863, A878 473 Metalloproteinaseinhibitor 3 P35625 I40, I42, A44, V46, L60, I64, V79, I82, L104, M113474 Copper-transporting ATPase P35670 V145, L147, V149, I161, V165,A183, I185, Y187, L197, V201, F206, C271, I279, V285, A297, V299, L311,I315, I363, 2 (EC 3.6.3.54) I365, I377, I381, V401, L413, I417, C490,L492, I494, V503, I506, L510, V516, V519, L520, A528, I530, Y532, I542,A543, I546, A553, I566, L568, I570, I582, L586, A595, A604, V606, F608,I618, I619, I622, A629, V820, C1079, V1106 475 Myosin-11 P35749 V38,A48, V58, V60, L62, M90, L93, A99, V101, L102, L105, Y109, L113, I114,Y115, Y117, F121, C122, V123, V124, V125, I133, I138, V139, Y142, M150,H153, I154, Y155, I157, A158, A161, M165, I174, L175, C176, A182, V191,I192, Y194, L195, A196, V198, A199, A221, I224, L225, A227, F228, A231,F242, F245, I246, I248, F250, V257, A259, Y264, L265, A271, F281, I283,F284, Y285, Y286, M287, M295, L299, L300, F309, L310, I317, F326, A332,M333, M336, I346, L347, V349, V350, V353, L354, L356, I359, F361, A370,A377, A378, V381, C382, L384, M385, F392, I396, L397, A417, F419, A420,V421, A423, L424, A425, A427, Y429, L432, F433, I436, L437, V440, L444,L455, I457, L458, F463, F471, L474, C475, Y478, L486, F487, Y499, I504,F511, L515, C518, I519, L521, I522, V531, L532, L534, L535, F549, L553,F563, F575, I577, I578, H579, V584, Y586, A588, W591, M596, V603, L607,F614, V615, W619, V653, Y657, L661, L664, M665, L668, F675, V676, C678,I679, I680, A692, V695, L696, L699, V704, I708, I710, F715, F721, F724,Y728, I736, A746, C747, M750, I751, I768, F769, F770, V774, L778, F806,W832, L885 476 Glutaredoxin-1 P35754 V6, I10, V15, V16, V17, F18, I19,C26, A29, I32, L33, I48, I57, L61, V73, F74, I75, L86, L95, L99, A104477 Vascular endothelial growth P35968 V136, I148, C150, L161, C162,A163, F185, I187, I192, A195, V198, C200, A202, I223, L244, C246, A248,V254, L292, factor receptor 2 I294, V297, Y305, C307, A309, V322 478Tyrosine-protein kinase P35991 V219, A221, L233, L235, Y241, A254, I264,A291, V427, I429, I432, F442, M449, L457, V458, Y461, V463, C464, BTK(EC 2.7.10.2) I470, I472, I473, L482, L486, L498, C502, V505, C506,A508, M509, L512, H519, L522, A523, A524, C527, V529, V535, V537, F540,V568, I580, W581, F583, V585, L586, M587, W588, I590, I610, A622, I629,M630, C633, W634, F644, L647, I651 479 Chitinase-3-like protein 1 P36222L24, V25, C26, Y27, Y28, C41, L46, L50, C51, I54, I55, Y56, F58, A59,L76, Y77, L80, L90, L93, L94, V96, F101, F106, I109, A110, F119, I120,V123, L127, F132, L135, L137, A138, W139, F150, L153, I154, M157, F161,L172, L173, L174, A176, A177, L178, A180, I185, I191, I194, L198, F200,I201, I203, H218, H219, L222, A240, V241, M244, L254, V255, M256, I258,F265, V274, A276, A295, Y297, I299, V316, Y318, A319, W325, V326, Y328,V334, V338, L341, A349, M350, V351, A353, L354, F359, F370, L372, A375,I376 480 Phosphoglucomutase-1 P36871 L22, V26, Y35, A36, F39, I40, I43,I44, A55, L57, V58, V59, A70, I71, I74, A75, I77, A78, A79, I83, L86,I88, L94, A98, V99, I103, I106, I112, I113, L114, A116, F127, I129,I147, C160, L163, V165, F184, V186, V192, Y195, L199, L208, L212, L218,I220, I222, A224, V228, Y232, V233, I236, L237, L241, F257, A269, L272,M276, F283, A285, A286, F287, M295, I296, L297, V304, V310, A311, V312,I313, I320, F323, F331, A332, M335, L341, A345, F362, L371, L373, C374,I386, L392, W393, A394, V395, L396, A397, W398, L399, I401, V409, I412,L413, F424, V433, A438, M441, L445, M449, F454, V468, L490, L492, F494,I500, V501, F502, I514, L516, Y517, I518, I528, L536, L539, A543, L549481 Receptor-type tyrosine- P36888 L143, L182, C231, A233, L268, I270,C272, A274, C330, F369, F418, A420, A443 protein kinase FLT3 (EC2.7.10.1) 482 Bone morphogenetic protein P36894 A428, I437, V450, V473,V496, L499, W504, A509, L515, L521, M524, V530 receptor type-1A 483Activin receptor type-1B P36896 A401, Y410, H423, V446, M469, M472,W477, A482, L488, L494, L497, V503 (EC 2.7.11.30) 484 TGF-beta receptortype-1 P36897 A399, F408, H421, V444, M467, I470, W475, A480, L486,L492, L495, I501 485 Guanine nucleotide-binding P36915 I363, C365, V366,F368, L376, I377, L380 protein-like 1 486 Tumor necrosis factor P36941C80 receptor superfamily member 3 487 Pigment epithelium-derived P36955L54, A55, A57, F61, L65, Y66, V78, L80, V85, A86, A88, L89, L92, A96,I104, L108, Y122, L125, V129, V143, F144, factor F154, L158, V184, M188,I205, L207, L208, V210, A211, F213, F231, M244, C261, A264, I274, I275,L293, I298, A310, V314, L317, V325, L329, L337, I346, L353, H358, A360,F362, Y388, L390, F394, I395, F396, V397, L398, L407, F408, I409, I412488 Serine/threonine-protein P37023 L405, V418, V441, L464, M467, W472,L483, L489, I492 kinase receptor R3 489 TGF-beta receptor type-2 P37173C51, C61, C84, V85, A86, V87, V100, C121, F133, C136, C138, I147 490Electron transfer P38117 V6, L7, V8, V13, A45, V46, A49, V61, I62, A63,V64, I75, A78, L79, A83, I87, H88, V89, V91, A105, V107, L108, L111,flavoprotein subunit beta A112, L119, V120, A139, A150, L160, V162,A179, V180, V181, A183, A201 491 40S ribosomal protein S19 P39019 V6,F14, L18, A19, F53, A57, A58, A61, L64, V99, A100, V103, L104, V113,L131, A135 492 60S ribosomal protein L3 P39023 A45, F46, L47, I56, V76,I78, V79, M84, V87, I89, V105, C114, M153, I160, V162, A164, H165, M168,A178, V185, L194, A197, V207, I217, V219, I220, V222, V231, I284, I314,F320, F330, V331, M332, L333, L345, L347, I368, M382 493 Collagenalpha-1 P39060 M1454, V1461, I1467, V1469, L1581, L1583, V1584, A1585,L1586, A1600, C1604, A1608, A1619, F1620, L1621, L1628, I1631, V1632,I1642, W1654, L1657, V1679, W1685, V1690, W1691, H1692, C1706, W1709,A1720, L1723, L1728, L1729, C1736, I1741, V1742, L1743, C1744, I1745 494Glial cell line-derived P39905 V127, F190, A205 neurotrophic factor 495Thrombopoietin P40225 L33, L56, V60, L62, A81, I84, L85, V88, L91, V95,A98, L111, L114, V118, I148, F149, F152, L156 496 Thrombopoietinreceptor P40238 L30, L31, C40, F41, F45, L48, C50, F51, W52, L65, Y67,C77, C93, F95, V101, L103, F104, L107, L109, V111, V127, V130, L132,A134, I139, A141, L150, I152, W154, F164, L165, Y167, L234, L246, Y252,W269, W272, L396, I401, L406, L408, W410, A418, Y423, Y427, W435, V437,L438, A444, L449, L451, Y457, A463, Y470, W474, W477 497 B-cell antigenreceptor P40259 V61, M63, C65, W76, A105, L107, I109, Y120, C122complex-associated protein beta chain 498 Alcohol dehydrogenase classP40394 A24, A25, V26, L27, F34, I39, V41, V49, I51, I53, A55, I58, H64,V65, V76, I77, V78, H80, A82, V96, V102, I103, L105, 4 mu/sigma chain(EC L107, C116, C124, L135, A136, F142, C144, V149, H151, F152, F158,V163, V164, V169, A170, I172, A176, V181, 1.1.1.1) C182, L183, I184,F188, Y192, A194, A195, C207, V208, V209, F210, L212, L217, V219, I220,C223, I231, I232, I234, A244, I253, V265, L266, V274, F278, A290, L291,C294, V302, V303, F331, V340, L343, V344, L354, L357, F364, I367, F371,V383, L384 499 Leptin P41159 I35, I38, L72, M75, L79, Y82, I85, I97,L101, L104, L108, A112, A146, L150, L154, M157 500 Extracellularcalcium- P41180 A46, V115, I135, F320, A321 sensing receptor 501Aquaporin-2 P41181 I112, L116, A127, C181, M183, A186, A190, A192 502Glycine--tRNA ligase (EC P41250 M124, L128, F133, A137, L157, I161,W165, F169, L189, V203, A214, L218, L222, M239, L254, L280, A301, I304,F305, 3.6.1.17) F308, A323, A324, A349, I351, F354, V368, A369, L373,A380, A387, L392, A395, I401, V405, L406, F409, I410, I413, Y416, L417,V420, L427, F429, W445, A447, I458, V459, C461, C466, L469, L480, A482,A503, I504, V515, I521, I542, L551, V574, I575, F579, L581, I584, M585,Y586, V588, F589, F593, F605, F607, V611, A612, C616, V618, L619, F627,L634, L638, V643, Y658, V666, A667, F668, V670, I672, A684, L686, I695,A697, L702, I705, V706, V719 503 T-lymphocyte activation P42081 A36,L38, C40, L53, V54, V55, L95, L97, L100, C110, I111, I112 antigen CD86504 Glutamate receptor 1 P42261 I25, I27, L30, F31, A41, F42, L46, L55,M70, F74, V82, A84, I85, F86, V94, L97, C101, V106, F108, I109, F113,F121, V122, L123, L125, L129, A132, L133, I136, I137, F145, V146, Y147,V161, A165, I177, L192, V200, V201, V202, C204, L209, L213, I216, I217,Y228, I229, L230, A231, L233, F235, F243, A248, V250, F253, V256, I266,W270, V281, A291, L292, V297, V299, M300, A303, F304, L307, A320, I337,A340, L341, L349, V353, L366, V368, Y409, I410, V411, Y419, V420, L422,F429, Y435, Y438, C439, V440, L442, A443, A444, I446, A447, L456, A466,M477, V478, L481, A486, V488, A489, V490, A491, L493, I495, I503, F509,L512, I514, I516, M517, I518, I647, L653, A654, Y661, F672, F673, M684,Y687, M688, V695, V697, M704, V707, Y714, A715, Y716, L717, L718, Y725,Y746, I748, A749, V760, A763, V764, L765, L767, L772, L773, L776, W780,W781 505 Glutamate receptor 3 P42263 I34, I36, L39, F40, A50, F51, V55,F69, L71, V86, F90, V98, A100, I101, F102, M110, L113, C117, F124, V125,F129, F137, V138, I139, M141, L145, A148, I149, L152, L153, F161, V162,Y163, I177, A181, V193, M209, Y217, L218, I219, C221, I226, L230, V233,V234, Y245, M246, L247, A248, L250, F252, V260, A265, I267, F270, V273,V280, F283, W287, A298, A301, L303, A308, L309, A313, I314, V316, I317,A320, F321, L324, A337, I354, A357, L358, M366, I370, I383, V385, I425,V426, V427, Y435, V436, Y438, L445, Y451, Y454, C455, V456, L458, A459,Y460, I462, A463, L472, A482, M493, V494, L497, A502, I504, A505, V506,A507, L509, I511, I519, F525, L528, I530, I532, M533, I534, I665, L671,Y679, F690, F691, M702, Y705, M706, V713, V722, V725, F732, A733, F734,L735, L736, Y743, Y764, V766, A767, V778, A781, V782, L783, L785, L790,L791, L794, W798, W799 506 Phosphatidylinositol 4,5- P42336 M16, L21,V22, C24, L25, L26, M30, I31, V32, C36, L42, I45, L49, A53, L61, I69,F70, V71, V73, F82, F83, L89, L92, L94, bisphosphate 3-kinase F95, L99,V101, I117, A120, I121, V125, F128, V136, F139, I143, L144, C147, A150,A163, Y165, I181, I190, V192, catalytic subunit alpha V193, I194, L209,I211, V220, I221, A222, A224, L239, L244, L252, V254, C255, C257, Y260,F261, L262, L267, Y270, isoform Y272, I273, C276, L285, L293, L327,I330, L334, I336, I338, A341, I354, Y355, V356, I360, Y361, V376, L387,Y389, I393, L396, A399, A400, L402, C403, L404, I406, C407, V409, C420,L422, A423, L429, F430, L443, L445, L452, L456, V461, L473, L475, V484,I492, A496, L531, I534, L540, L551, C558, V559, I564, L565, L568, L569,L570, V580, A581, M583, V587, I593, A598, M599, L601, L602, V611, F614,A615, V616, C618, L619, L628, Y631, L632, L635, V636, V638, L639, L648,L649, V650, L653, L654, A657, L658, I663, H665, F667, F668, W669, L671,V680, F684, L686, L687, L688, Y691, C692, A694, C695, Y698, L699, L702,V706, A708, M709, L712, L715, I718, L719, L735, M739, F744, A747, L748,F751, L755, L761, L764, C769, I771, L779, L781, W783, I788, M789, L792,L793, I799, F801, L807, L812, L814, I816, I817, M820, W824, L831, M833,L834, L839, L847, I857, I860, L877, H878, L881, A893, L896, F897, C901,A902, Y904, C905, V906, A907, F909, I910, L911, I913, I921, M922, V923,L929, F930, H931, F934, F937, L938, F954, F960, L961, I962, V963, I964,C971, F977, F980, C984, A987, Y988, A990, I991, A995, F998, I999, L1001,F1002, M1004, M1005, M1010, L1013, F1016, I1019, Y1021, I1022, L1026,A1035, F1039, M1043, W1051 507 Protein AF-9 P42568 V7, L11, L13, H15,A17, V34, V36, F47, V48, V51, V52, F53, Y71, I82, L83, I85, V87, F89,Y102, L104, F131, L135, I522, I526, I530, V555, L558 508 Dipeptidylaminopeptidase- P42658 V131, V133, F156, V165, A201, L202, V220, L242,A245, I255, F256, I257, I262, W291, L292, Y293, A303, A314, I318, likeprotein 6 L328, L356, H357, V358, L361, L368, M370, Y382, I383, V394,A395, V396, W398, I407, C411, A413, W429, F447, H462, I463, V487, I500,F502, L514, A517, V520, L528, C536, F550, C554, V564, H565, L606, M608,I610, L624, L625, M649, V650, A655, V656, V657, L672, V676, M689, V692,M695, V706, A707, V708, Y716, L717, I721, F733, C735, A738, I742, F745,A749, A751, L757, Y767, V772, V776, L785, I786, I787, H788, I795, F797,H799, L807, I839, F843 509 Leukemia inhibitory factor P42702 V81, I112,L134, L153, V170, V176, L211, H216, V218, I220, V254, F269, C270, C271,V277, A280, I299, V314, F316, receptor I327, A329, I349, C351, W353,L371, F397, Y406, F408, L410, A412, I427, V431, L451, F459, C466, I468,V494, I509 510 Wiskott-Aldrich syndrome P42768 F258, L267, L270, F271,L281, I290, F293, I294, V303, L326, I438, L470 protein 511Growth/differentiation factor P43026 C400, F409, C433, A447, I476, C498,C500 5 512 Platelet-activating factor P43034 V111, M123, V124, A126,I132, L146, V153, L165, A166, C168, I174, L176, W177, M188, V195, V198,I207, V208, acetylhydrolase IB subunit A210, I216, W219, V237, V240,I249, A250, C252, V258, V260, L272, V279, C281, L311, L312, I320, L334,V341, alpha I353, L354, C356, A357, L362, W365, Y367, V383, V396, V404,V406 513 Cathepsin K (EC 3.4.22.38) P43235 I44, L48, Y126, V130, C136,C139, W140, A141, A147, L148, L159, L162, L167, V168, V171, A185, F186,V189, I195, Y201, M211, A219, C221, I227, L235, A238, V239, V242, V245,V247, A248, I249, A251, F256, F258, Y264, Y265, L274, H276, A277, V278,L279, A280, V281, Y283, W292, I294, W302, I308, M310, A311, A317, C318,I320, A321, L323, A324 514 Hemagglutinin [Cleaved P43258 A11, L13, C14,L15, A19, V26, V36, L42, V43, I51, C52, I58, C64, L66, I67, L70, L71,C76, F79, L86, F87, V88, F94, into: Hemagglutinin HA1 C97, Y98, Y100,Y105, A106, L108, V112, A113, L118, F125, A138, C139, F147, F148, L151,L154, L164, Y178, W180, chain; Hemagglutinin HA2 V182, H183, H184, Y195,V202, V204, I230, I232, Y233, I236, V237, V242, L243, I245, L251, I252,A253, F258, I274, chain]/strain A/Duck/Hong C281, I282, I288, V309,L316, A317, A334, W343, Y351, A373, A425, L447, L455, C466, F467, I469,H471, C473, C477, Kong/64/1976 H3 I478, I481, A495 515 Hemagglutinin[Cleaved P43259 A11, L13, C14, L15, A19, V26, V36, L42, V43, I51, C52,I58, C64, L66, I67, L70, L71, C76, F79, L86, F87, V88, Y94, into:Hemagglutinin HA1 C97, Y98, Y100, Y105, A106, L108, V112, A113, L118,F125, A138, C139, F147, F148, L151, L154, L164, Y178, W180, chain;Hemagglutinin HA2 I182, H183, H184, Y195, V202, V204, I230, I232, Y233,I236, V237, V242, L243, I245, L251, I252, A253, F258, I274,chain]/strain A/Duck/Hong C281, I282, I288, V309, L316, A317, A334,W343, Y351, A373, A425, L447, L455, C466, F467, I469, H471, C473, C477,Kong/231/1977 H3 I478, I481, A495 516 Hemagglutinin [Cleaved P43260 A11,L13, C14, L15, A19, V26, V36, L42, V43, I51, C52, I58, C64, L66, I67,L70, L71, C76, F79, L86, F87, V88, F94, into: Hemagglutinin HA1 C97,Y98, Y100, Y105, A106, L108, V112, A113, L118, F125, A138, C139, F147,F148, L151, L154, L164, Y178, W180, chain; Hemagglutinin HA2 V182, H183,H184, Y195, V202, V204, I230, I232, Y233, I236, V237, V242, L243, I245,L251, I252, A253, F258, I274, chain]/strain A/Goose/Hong C281, I282,I288, V309, L316, A317, A334, W343, Y351, A373, A425, L447, L455, C466,F467, I469, H471, C473, C477, Kong/10/1976 H3 I478, I481, A495 517Neuronal acetylcholine P43681 A141, H142, A155, V165, I189, L191receptor subunit alpha-4 518 2-C-methyl-D-erythritol 2,4- P44815 H11,L19, I20, I21, V26, F32, I33, A34, V40, A41, L42, H43, A44, L45, A48,I49, L50, A52, A53, I58, L77, L78, A81, V85, cyclodiphosphate synthase/I92, V95, I97, I99, M106, I110, M113, A115, I117, A118, L121, I125,V128, A132, I147, A148, C149, A151, A153, L154, strain ATCC 51907/DSML155, I156 11121/KW20/Rd 519 Aspartoacylase (EC P45381 I11, V14, A15,I16, F17, V31, I41, A57, L69, F73, A93, I96, F100, I111, I112, F113,M122, C124, L126, L128, L136, I137, 3.5.1.15) M139, F140, I143, V154,L156, I170, V175, I177, V179, M195, M198, A202, L203, F205, I206, F209,I220, V222, I225, A241, L247, V281, V283, A294, F295, A296, I308 520Short/branched chain P45954 A72, I76, M83, V93, L97, M103, I105, V107,V122, L123, V124, I125, L128, A129, A133, V135, A136, C139, I146, L149,specific acyl-CoA I150, L163, L166, C175, A181, A192, L201, I208, A211,A214, L216, F217, L218, V219, M220, A221, I232, F235, dehydrogenase,L236, V237, L244, C261, L263, V268, V270, L276, A286, I295, I297, A298,A299, M301, L302, L304, A305, C308, I316, mitochondrial L332, L343,A346, A353, A354, A367, A370, A374, A378, C385, V400, A407 521 ChemokineXC receptor 1 P46094 A26, W27, V28, F29, A30, L32, A33, V36, L37, C39,L40, F42, L46, V47 522 Large proline-rich protein P46379 V19, V21, A35,V39, F42, I46, V50, L59, L72, V77, I82, L84 BAG6 523 Vesicle-fusingATPase (EC P46459 V23, I74, F121, V514, A551, A554, L623, L627, L6773.6.4.6) 524 Neurogenic locus notch P46531 C423, C438, C449, C456, C461,C487, C525, C942, C1056, C1180, C1454, C1467, C1496, C1509, L1515,C1536, L1574, homolog protein 1 V1575, V1576, V1577, V1578, L1585,F1592, L1596, L1600, I1616, V1676, L1678, I1680, C1685, A1696, V1699,A1700, L1703, A1705 525 40S ribosomal protein S10 P46783 L15, F16, M21,A23, V45, A48, M49, L79 526 E3 ubiquitin-protein ligase P46934 G451,Y463, L499, L529, L563, Y785, F858, F948, M964, I979, L988, A990, L992,F996, A1008, W1011, F1012, I1015, NEDD4 (EC 6.3.2.—) M1019, F1027,F1054, F1056, I1057, V1060, A1061, M1063, A1064, V1065, L1071, F1075,Y1080, M1083, L1084, M1093, L1104, F1119, I1121, V1143, Y1151, V1155,M1168, F1171, F1175, L1178, I1179, I1184, F1187, L1192, M1196, C1197,W1207, V1223, I1224, F1227, W1228, A1230, V1231, L1242, L1243, V1246,F1257, L1260, F1269, V1271, L1290, L1292, L1301, L1305, I1309 5273-hydroxyanthranilate 3,4- P46952 L32, I48, L64, V66, L85, V89, V100,V104, L116, Y119, L194, V211, A213, L230, L248, L255, A272 dioxygenase(EC 1.13.11.6) 528 F-actin-capping protein P47756 A9, L25, L39, L60,V119, Y120, A129, V131, L133, I134, H152, V154, V156, A165, Y167, L169,V173, M174, V217, subunit beta M220, I224 529 Tumor necrosis factorligand P48023 A147, L149, L160, L181, I183, Y189, V191, V195, F197,L207, H209, V211, L257, V259, F276, L278 superfamily member 6 530Stromal cell-derived factor 1 P48061 I59, A61, I72, I79 531 Glycinereceptor subunit P48167 V80, V82, V84, I86, Y101, V103, I105, W111,L116, L128, L163, I165, V171, I179, L181, C183, L187, F190, C197, betaM199, L201, L211, F213, C255, V256, V258, F260, L262, V273, I280, V281,F288, L309, A328, L329, L333, C336, V350, M353, A370, A470 532Transcription factor SOX-9 P48436 V114, A116, L123, L135, L139, F154 533G protein-activated inward P48544 W108, A139, L168, A206, V207, I208,L217, V221, I234, A236, L238, L252, I257, L274, M289, V301, V303, L305,rectifier potassium channel 4 A318, Y322, F351, A368 534 T-complexprotein 1 subunit P48643 A33, A41, M48, A75, I77, I87, M91, V109, V110,A113, L116, L123, I133, A140, A144, A169, L173, A186, A189, A192,epsilon V204, I229, M239, A246, I248, A249, I250, L251, F255, I289,I292, A297, L299, A300, I301, C302, A310, L314, L319, A321, I330, I333,A356, V359, V373, I374, I385, F386, I387, L402, A405, V408, I409, L412,V419, A424, A425, I427, A430, V433, A437, F451, A452, A454, A461, V477,L510, A520, I527 535 Protein ERGIC-53 P49257 V64, I80, V82, A83, V93,W94, A99, V106, V108, F110, V112, A120, L123, A124, W126, Y127, A128,V137, F138, V147, F150, F151, I165, I167, I168, I174, F194, V201, A203,I205, L212, V214, I216, A231, F244, I246, A248, H257, V259, F262, F265536 Alpha-aminoadipic P49419 L33, L42, Y55, C70, I77, A78, V80, V92,A95, A98, W102, V114, I117, L121, I125, L128, L131, V132, L134, M136,semialdehyde V147, Y150, V151, I153, C154, A157, I179, L187, V188, I190,I191, V198, A199, V200, Y201, A206, I207, A208, M209, dehydrogenaseI210, C211, V214, C215, L216, W217, L225, I226, V228, A229, V230, I234,L238, A246, I247, L250, C252, I257, A260, M261, A262, V267, L269, L270,V286, L294, A302, I303, I304, A305, V314, A318, A321, A326, A333, L336,F337, I338, V346, L350, Y369, L372, F381, A384, V385, A388, Y408, V409,I413, V414, A424, A430, I432, L433, V435, F436, F438, V444, L455, I459,F460, W470, Y516 537 Alanine--tRNA ligase, P49588 I10, F14, F17, F18,A42, A44, M46, F49, A69, A70, C75, I76, F97, L101, W104, C115, M117,A118, L121, L122, Y134, cytoplasmic (EC 6.1.1.7) V135, F138, C152, W156,C184, C187, I190, H191, A200, L212, W215, L217, F219, I220, I238, M242,L244, L247, V248, Y258, F263, Y266, I270, A288, A294, Y295, V297, L298,A299, H301, A302, I305, V307, A308, L309, L324, I327, L328, A331, V332,A335, L339, F346, A347, L349, V350, V353, L357, F361, I375 538Prolactin-releasing peptide P49683 A44 receptor 539 Cartilage oligomericmatrix P49747 C287, C292, C328, C351, C387, C410, C448, C484, C504,F531, L539, L570, A571, V572, F577, F582, H587, V588, protein Y596,A597, I600, F601, F609, Y610, V611, M613, A629, A631, I635, L637, A639,V640, L650, A653, L654, W655, V664, W684, L686, H688, Y694, I695, V697,M717, L722, V724, F725, C726, I732, W734, A735, L737, C741 540Presenilin-1 P49768 V89, C92, M93, V96, A136, I213, L226, A231, A234,L235, A246, V261, A285, V379, L381, F386, Y389, V391, L392, V393, A396,C410, I414, I439, M457 541 Bis(5′-adenosyl)- P49789 F23, A24, V36, L37,V38, C39, L58, V65, V69, H94, V99, A139, L142 triphosphatase (EC3.6.1.29) 542 Presenilin-2 P49810 V95, C98, M99, V102, I219, L232, A237,A240, L241, A252, V267, A291, L362, F367, Y370, L373, V374, A377, C391,I395, I420 543 Glycine amidinotransferase, P50440 V66, W72, V78, I79,V80, A83, A86, C87, V88, V95, A97, Y107, F115, A123, I127, M130, C131,L134, L163, Y164, mitochondrial (EC 2.1.4.1) A166, M167, I171, L172,I173, V174, I179, I180, A182, M184, A185, W186, A195, Y196, I200, Y203,M218, L222, I229, V245, C252, F253, A255, A256, I259, A261, I265, F266,A267, V272, M281, I294, I304, F308, I310, I311, V316, L317, F330, M353,M360, V362, L363, M364, L365, V370, M371, V372, I379, F383, V393, I395,A398, L401, F405, H406, W408, C410, V412 544 Serpin H1 P50454 L102,V107, A109, A203, V226, M271, L324 545 Dynamin-2 (EC 3.6.5.5) P50570V13, L16, F20, L29, I34, A35, V36, V37, A42, V47, L48, F51, V52, F56,L57, L69, L71, L73, I74, A81, F83, F91, V97, I120, L122, V124, V129,L132, L134, I135, L137, I140, I152, I156, I160, I164, I171, L172, A173,V174, A177, A186, A190, V193, I201, V203, I204, L207, A216, I232, V234,F259, Y265, A269, L277, L281, L285, I289, L293, L300, L304, L305, F336,F340, F370, L374, L384, I388, I392, A408, F409, V413, V417, C424, C427,V428, V431, L435, V439, C442, L452, I459, V460, I475, I479, L526, I528,Y541, F543, L545, L550, W552, I572, F586, A587, I588, F589, I603, L605,C607, V613, W616, F620, V625, V664, M675, I679, M683, I691, L695, L699,L729, A732 546 Palmitoyl-protein P50897 V36, V88, V95, L99, L105, F120,A123, V124, H143, F147, C160, I163, V181, A183, Y195, F201, L202, A203,I205, thioesterase 1 Y215, L222, V228, F230, L258, L263, L269, L283 547Sodium/potassium- P50993 H42, L44, L49, A66, L102, A106, C109, V133,V138, V169, I170, V183, V184, L188, V189, A199, L201, I203, C209,transporting ATPase subunit V211, C241, F242, C247, A252, I255, V256,A272, I286, A297, A318, I320, F321, I325, L334, V340, A346, C354, V362,alpha-2 C372, L379, M384, A387, M389, W416, A418, L419, I422, A423,L425, C426, A429, V440, A453, L454, V465, L488, I490, H491, H500, V501,L502, V503, M504, I511, L519, Y539, L542, F552, C553, L557, L580, C581,F582, V583, L585, M588, A594, V596, A599, V600, C603, A606, I608, I611,M612, A621, A623, A625, I630, I631, A642, A643, A657, A659, I685, V686,F687, A688, I698, V699, C702, V709, V716, A721, L722, A725, I727, I729,A730, M731, I746, L747, F752, V759, L764, I765, Y775, L777, F790, L799,I807, A816, L819, L841, V842, L846, A850, I854, Y866, I869, L870, F875,L880, W887, C915, A918, F919, F920, A921, I923, V924, V925, V926, L931,I933, C934, L951, L955, A962, L975, M977, A988, I995, L1006, Y1020 548Ras-related protein Rab-7a P51149 L9, V11, I12, I13, L14, V19, L24, M25,Y28, V52, V57, M59, I61, A65, Y78, C83, C84, V85, L86, V87, F88, V90,L99, F106, F120, V121, V122, L123, V134, A139, C143, A156, V162, A165,F166, I169, A170, A173 549 Ras-related protein Rab-27A P51159 L13, Y27,L96 550 Transcription activator P51532 M1462, I1465, V1466, V1469,I1501, F1507, I1510, I1514, L1525, V1529, C1533, A1536, L1553, F1557,V1560 BRG1 (EC 3.6.4.—) 551 Galactokinase (EC 2.7.1.6) P51570 A16, V32,A34, L53, V64, V73, A107, V110, V113, A120, A127, V128, V130, V133,L139, A143, V147, A148, F152, L153, A167, C170, A173, V211, I222, C243,V246, L255, L263, A266, A278, H280, V281, A291, A292, A294, Y318, C322,L328, V329, A332, C351, L356 552 Methyl-CpG-binding protein P51608 L124,F132, L138, F142 2 553 Fatty aldehyde P51648 V8, L27, A29, L30, M33,V34, I41, I45, L49, V56, V61, V64, I68, M71, L75, V104, V105, L106,I107, F115, L117, I119, dehydrogenase (EC 1.2.1.3) L122, I123, A125,I126, A127, A128, A131, V132, I133, I134, L150, L151, L159, Y160, L173,F182, V193, A196, A197, C214, I216, V225, C226, I229, Y234, C237, I247,L248, C249, I257, I261, I282, F288, I291, L294, I313, A314, V317, L318,V327, M328, I332, I336, L337, I339, A348, L359, A360, L361, Y362, V363,F364, M374, V388, Y410, F419 554 C-C chemokine receptor P51681 Y187 type5 555 N-sulphoglucosamine P51688 A25, L26, L27, L28, L29, A30, L58, F60,A63, F64, V67, A75, L77, L81, M88, L107, L111, I120, I121, V126, V131,Y132, sulphohydrolase (EC I152, I155, V159, F162, F171, F172, L173,Y174, V175, A176, F177, F193, C194, I207, A232, L236, Y240, V250,3.10.1.1) V253, L257, L267, I276, F278, L285, V296, A311, V313, L318,I322, L323, L348, A351, M376, V379, L386, F408, L411, L438, L464 556Arylsulfatase E P51690 M61, L163, L292 557 Amyloid-like protein 1 P51693F395, A398, V409, L413, L467, L477 558 Potassium voltage-gated P51787W379, W392, I394, I396 channel subfamily KQT member 1 559 Chloridechannel protein P51800 V547, L558, A559, V567, Y579, V582, V594, L599,L618, L635, L641, A644, F648, V658, V668, M673, A676 ClC-Ka 560Ribosomal protein S6 kinase P51812 V85, A93, A98, I121, F129, V131,I146, L155, F165, V170, Y173, L174, A175, L177, A178, A180, L181, L184,L187, alpha-3 I189, I190, Y191, L194, I199, L201, H206, I207, L209,F212, A225, A236, H245, A249, W251, W252, F254, V256, L257, M258, M261,F268, I280, L281, L285, F290, A295, L298, L299, L302, A308, V318, I321,F327, L335, A347, C439, V450, I453, I464, I466, L467, Y470, I476, V491,V492, L501, L502, I505, L506, A516, L520, I523, V527, L530, V535, V536,H537, L540, I545, I557, I559, F562, M576, I601, L604, V606, L607, L608,Y609, M611, L612, F618, A619, I629, W645, A652, L655, V656, M659, L660,A670, V673, W678, V699, A702 561 Cytoplasmic tyrosine-protein P51813V442, V444, A461, L467, L472, V478, C479, V488, L497, L513, M516, C517,V520, C521, M524, L527, L537, A538, kinase BMX (EC 2.7.10.2) A539, C542,V544, V550, V552, V561, A580, V595, W596, F598, I600, L601, M602, V605,F606, V621, A637, M645, C648, F659, I666 562 Spermine synthase P52788L9, F11, L13, L26, F30, A36, L48, A49, Y51, A59, L61, I63, V69, L71,L73, I89, V93, Y134, I150, I152, I161, I163, I181, V194, L195, I196,L197, I204, L205, I208, V216, M218, V219, C229, V259, L260, Y263, V273,I274, I298, L299, M303, V305, L306, F313, V348, Y358, V360 563 Ephrin-A5P52803 V34, W36, I50, V52, L58, V60, Y77, L79, C102, F118, F130, Y138,I139, L154, V156, V158 564 Biliverdin reductase A P53004 V11, V12, V13,V14, V16, F42, A62, V70, A71, Y72, I73, H80, I84, F87, L88, V94, L95,V96, M100, A107, L110, H122, L136, L150, A166, F167, I170, L173, W175,L176, M201, V203, L205, L213, W215, F231, F258, I278, C281, L282, A285,I288 565 Collagen alpha-4 P53420 L1468, L1494, Y1495, L1507, Y1541,W1542, L1543, V1563, C1566, A1567, V1568, C1569, A1571, F1601, H1604,C1622, F1631, L1632, C1634, C1641, C1683, V1685, C1686, V1687 566Dipeptidyl peptidase 1 (EC P53634 C30, L35, W39, F41, V66, L68, A74,F84, I86, I87, F92, I94, F102, A103, F105, H127, W134, C136, F137, Y259,A262, 3.4.14.1) M264, M266, A269, I271, L283, V288, Y294, Y304, L305,I306, A307, A311, L316, V317, Y347, Y352, M360, L364, M370, A371, V372,F374, F380, V407, L408, L409, V410, W423, V425, F439, I441, I450, A454,A456, A457 567 DNA polymerase subunit P54098 F139, A143, A153, L157,W175, Y178, A194, L195, V196, F197, C202, A212, V213, A214, I215, A219,W220, C224, gamma-1 (EC 2.7.7.7) A242, L244, A253, L265, V266, V267,A276, I278, Y282, M289, M297, H298, A300, I301, L304, V359, M393, A397,V400, V406, F407, V422, A425, M427, L428, V432, Y434, L435, V437, W441,A448, L463, A467, F610, I798, W801, A804, I808, A839, L841, A847, V870,L874, A876, V878, A880, V887, A889, V891, I898, A899, A900, L902, A908,A915, A936, A982, A1045, L1061, C1077, I1079, A1082, W1099, V1100,V1101, A1105, V1106, Y1108, H1110, L1111, L1113, V1114, A1115, M1116,L1119, C1130, Y1139, L1140, V1141, A1149, A1150, A1152, L1153, C1162,M1163, A1165, L1168, A1178, A1182, V1183, C1197, A1217, L1218 568Tyrosine--tRNA ligase, P54577 I14, L27, L36, I38, Y39, F53, M56, I59,F62, C67, V69, I71, F73, H77, A78, A85, V94, Y96, Y97, V100, I101, M104,L105, cytoplasmic (EC 6.1.1.1) Y129, L136, A171, L172, A181, F183, I191,F192, A195, L199, V208, H209, L210, M211, I232, L234, V241, L245, V260,L261, I264, V267, I277, Y289, L295, F299, V304, L309, V313, L317, L321,I324, L336, A339, A340, I370, V372, I375, I392, V394, V402, V403, L406,L415, V420, V421, V422, L423, L440, L441, C442, A443, L455, V469, L491,F495, I497, A503, F510, I517, C519, I527 569 Ephrin type-A receptor 4P54764 I67, V72, L84, I89, A94, V97, Y98, I99, I101, F103, L105, V114,F122, L124, I148, V157, V173, F181, Y182, L183, (EC 2.7.10.1) A184,F185, A190, I192, A193, L194, V195, V197, V199, C204, A212, F214, M245,C247, C273, C276, C325, V344, L346, V398, I400, Y409, F411, I413, A415,V419, V434, A440, V447, V457, L459, V476, I500, Y509, F511, V513, A515,A519 570 Alpha-N- P54802 V32, L35, V36, L67, V75, V77, V83, A84, A85,A86, L89, Y92, C99, Y132, I154, M157, A158, I162, L164, A165, A167,acetylglucosaminidase (EC I174, V178, A181, I189, A197, F198, A200,L230, M233, F236, V241, L242, F245, V253, F271, L281, I291, F295, L296,3.2.1.50) Y309, L327, V334, M338, A345, F354, A368, L378, L379, V380,V390, F397, F402, I403, W404, C405, M406, L407, L420, A430, A444, V453,V454, L457, V475, F478, A479, A490, A493, V501, L517, V518, V536, F537,A539, W540, L550, F556, L560, L561, L563, A567, V568, L571, V572, Y575,L584, L591, V597, L598, A599, L602, L603, L606, V609, L610, F616, L618,L622, A625, A635, Y638, L646, L648, W649, A659, L666, V667, Y670, Y671,W675, F678, L679, L682, V701, V709, V724, A727, Y734 571Galactocerebrosidase P54803 L83, L95, L98, F437, V576, V607 572Adenylate kinase 2, P54819 I16, A18, V19, L20, L21, A26, A32, L35, F39,V41, L64, V80, L82, I83, F96, L97, L98, F101, A108, L111, M115, L122,mitochondrial V125, I126, F128, L134, L135, I139, L143, H145, A182,L183, L187, L197, Y200, Y201, I210, A212, I223, F227 573 Allograftinflammatory P55008 L24, L47, F50, Y54, F57, L59, I65, L70, M73, L74,L86, I90, F101, Y103, F106, L107, A116, L118 factor 1 574 Transitionalendoplasmic P55072 L26, V28, V38, V39, L41, M46, V57, L59, A67, V68,C69, V71, I82, M84, V88, L92, V94, I100, I102, C105, I114, V116,reticulum ATPase I119, Y134, L135, F139, L153, V154, V161, F163, V165,V166, C174, V176, A177, V181, C184, A214, I216, V220, I241, L242, L243,Y244, I254, A255, A257, V258, A259, I269, I274, L286, A289, F290, A293,A299, I300, I301, F302, I303, L306, I309, A310, I324, V325, L328, L329,M332, L335, V341, I342, V343, M344, A345, A346, I353, L357, F363, V367,I369, L381, V399, A400, H406, V407, L411, L414, C415, A418, A419, A422,A439, V447, F452, A455, L489, V493, V514, L515, F516, L527, A528, A530,I531, A532, F539, I540, I542, L547, L548, V559, F563, A566, C572, V573,L574, F575, F576, I582, V600, I601, M608, I619, I620, A622, L639, I645,L657, A676, L687, I690, A694, I731, H735, A739, V747, I752, L762 575Fibroblast growth factor 8 P55075 L74, V83, V85, A93, A95, A102, I126,C127, M128, I135, C145, F147, A158, M169, A170, F171, V190, F192 576Laminin subunit beta-2 P55268 C519 577 Cadherin-8 P55286 V70, F109,I118, A120, L124, L134, A138, I154, I155, V157, V176, V189, A223, I224,I225, V242, I244, A246, L262, V264, A300, F324, L353, V355, A357, V378,I380 578 Cadherin-15 P55291 L138 579 FAD-linked sulfhydryl P55789 A114,A115, A146, L153, F166, L170, C171 oxidase ALR (EC 1.8.3.2) 580Eukaryotic translation P56537 F7, I13, A17, Y23, C24, L25, V26, A27,F34, F38, V49, I53, I59, V64, L70, L71, V72, I84, V97, L104, V107, A115,L116, initiation factor 6 V117, L129, L133, V142, V148, V153, L160,V161, L173, L177, V179, V186, I193, A194, M197, V198, C203, A204, F205,C206, V218, F222 581 Ubiquitin-associated and P57075 L28, A38, A41, L42,A53, L57 SH3 domain-containing protein A 582 Ras-related protein Rab-25P57735 V15, V16, L17, I18, V23, L28, L29, V47, A60, V61, A63, I65, A69,Y74, A76, Y81, Y82, A85, A88, L89, L90, V91, F92, L94, V103, L110, V120,M121, L122, V123, V135, A140, A144, A156, L157, V162, A165, F166, V169,L170, I173 583 Anthrax toxin receptor 2 P58335 F43, L45, Y46, F47, V48,L49, V55, I62, V66, L69, A70, L80, F82, I83, V84, F85, I91, I102, L109,I120, L124, A127, I131, I142, I143, I144, A145, L146, A159, A163, V173,Y174, C175, V176, V178, L186, I189, L206, I209, I213 584 Spikeglycoprotein/SARS- P59594 V328, V337, I345, A350, L374, V382, A384,F387, V388, V389, I397, A398, I405, A406, Y410, L412, C419, V420, CoV(Severe acute L421, A422, F483, V496, V497, V498, L499, V510 respiratorysyndrome coronavirus) 585 CD81 antigen P60033 Y127, L131, A134, V147,H151, C156, V169, L174, C190, I194 586 Phosphatidylinositol 3,4,5-P60484 L25, I33, A34, M35, A39, I50, V53, F56, L57, I67, Y68, L70, I101,F104, C105, L108, A120, A121, I122, H123, A126, trisphosphate3-phosphatase V133, M134, I135, C136, A137, L139, A148, A151, Y155,Y174, V175, Y180, L193, F195, M198, F200, F206, V217, anddual-specificity protein F241, V249, V255, F257, H259, M270, F271, F273,V275, F279, V317, L325, A328, F341, V343 phosphatase PTEN (EC 3.1.3.16)587 Interleukin-2 P60568 L34, L37, L38, L41, I44, L45, I48, M59, F62,F64, M66, L73, H75, L76, C78, L79, L83, L86, V89, L90, F98, L105, I106,I109, I112, V113, F123, I134, V135, F137, L138, W141, F144, C145, I148588 Proteasome subunit alpha P60900 A31, V40, A41, V42, C47, A48, V49,I50, V51, C78, V79, V91, A94, Y96, A99, L114, C115, I118, A119, C136,M138, type-6 (EC 3.4.25.1) I139, L140, I141, V151, C154, A165, A167,A168, V195, A198, I199, C201, L202, V217, V219, V220 589 Cell divisioncontrol protein P60953 I4, C6, V7, V8, V9, A13, V14, C18, L19, L20, F28,V36, F37, V42, V44, I46, Y51, L53, L55, A59, L70, Y72, V77, F78, L79, 42homolog V80, C81, F82, V84, V85, F90, V93, W97, V98, I101, C105, F110,L111, L112, V113, I117, L129, I137, A142, L145, A146, L149, V155, C157,A159, L165, V168, F169, A172, I173, A175, A176 590 Pterin-4-alpha-P61457 L17, W25, A33, I34, F40, A46, F49, V53, A57, V73, I75, L77, L85,L92, A93, I96, V99 carbinolamine dehydratase 591 Lysozyme C (EC3.2.1.17) P61626 C24, L26, A27, L30, M35, L43, A44, W46, M47, C48, L49,A50, I74, F75, I77, C83, C95, C99, L102, I107, A108, A110, V111, C113,A114, V117, V118, I124, W127, C134, V139, C146 592 Beta-2-microglobulinP61769 V29, Y30, L43, C45, V47, F50, H51, L59, L60, F82, L84, Y86, F90,Y98, A99, C100, V102, H104, W115 [Cleaved into: Beta-2- microglobulinform pI 5.3] 593 Transforming growth factor P61812 C317, C318, L319,F326, C350, L388, I390, C413 beta-2 594 Epididymal secretory proteinP61916 V37, C42, C47, Y55, V59, F61, I101, Y109, L124, W128, L130, L138,F139, C140, W141 E1 595 Ras-related protein R-Ras2 P62070 Y15, L17, V18,V19, V20, V25, L30, F34, V40, C55, I57, A62, L64, I66, L67, A70, M78,M83, F89, L90, L91, V92, F93, V95, F101, I104, F107, I111, V114, F120,M122, I123, L124, I125, L131, V137, L145, A146, A156, A158, V164, A167,F168, L171, V172 596 40S ribosomal protein S7 P62081 L27, L30, L36, L40,L43, I51, A59, I61, V64, F72, L79, V93, I95, L130, L133, V134, V156,F173, V176, Y177, V185 597 Actin, aortic smooth muscle P62736 A9, L10,V11, C12, C19, A21, A31, V32, F33, I36, V37, Y55, A60, L67, I73, M84,I87, W88, F92, L106, L107, A110, L112, M121, I124, M125, F126, F129,V131, A133, M134, V136, A140, V141, L142, L144, I153, V154, L155, V161,H163, V165, I167, L173, A176, M178, L180, L182, A183, L187, L191, I194,L195, A206, I210, V211, I214, C219, V221, A222, I250, I252, F257, C259,L263, F264, I276, I284, C287, I289, I291, L295, Y296, A297, V300, L301,Y308, I311, M315, I319, W342, I347, F354, W358, I359, I371, V372, C376598 40S ribosomal protein S26 P62854 A78 599 60S ribosomal protein L11P62913 L22, A36, L40, V70, V74, I82, L87, F105 600 Guaninenucleotide-binding P63092 L43, L44, L45, L46, I56, M60, I95, L99, A102,I103, I106, L113, I131, F146, A150, L153, V159, C162, C174, A175, F178,protein G I182, I185, F219, M221, V224, A243, I244, F246, V247, V248,Y253, F273, L282, V287, I288, L289, L291, L296, L297, V301, A337, I341,F345, A351, I372, C379, I383, H387 601 Inward rectifier potassium P63252V161, L245, I250, I267, L298, A362, F374 channel 2 602 Casein kinase IIsubunit beta P67870 F21, C23, V25, I30, L36, L39, A49, I53, A75, A76,L79, Y80, I83, H84, Y87, I88, I94, M97, F106, C114, M119, L120, V133,C137, F159, F163, L167 603 Actin, alpha cardiac muscle P68032 A9, L10,V11, C12, V19, A21, A31, V32, F33, I36, V37, Y55, A60, L67, I73, M84,I87, W88, F92, L106, L107, A110, L112, 1 M121, I124, M125, F126, F129,V131, A133, M134, V136, A140, V141, L142, L144, I153, V154, L155, V161,H163, V165, I167, L173, A176, M178, L180, L182, A183, L187, L191, I194,L195, A206, I210, V211, I214, C219, V221, A222, I250, I252, F257, C259,L263, F264, I276, I284, C287, I289, I291, L295, Y296, A297, V300, L301,Y308, I311, M315, I319, W342, I347, F354, W358, I359, I371, V372, C376604 Ubiquitin-conjugating P68036 A3, L7, I14, F22, W35, I39, Y46, A50,F51, I53, I55, F70, H76, I79, V104, I105, L108, L111, V112, L125, F136,A140 enzyme E2 L3 (EC 2.3.2.23) 605 Actin, alpha skeletal muscle P68133A9, L10, V11, C12, V19, A21, A31, V32, F33, I36, V37, Y55, A60, L67,I73, M84, I87, W88, F92, L106, L107, A110, L112, M121, I124, M125, F126,F129, V131, A133, M134, V136, A140, V141, L142, L144, I153, V154, L155,V161, H163, V165, I167, L173, A176, M178, L180, L182, A183, L187, L191,I194, L195, A206, I210, V211, I214, C219, V221, A222, I250, I252, F257,C259, L263, F264, I276, I284, C287, I289, I291, L295, Y296, A297, V300,M301, Y308, I311, M315, I319, W342, I347, F354, W358, I359, I371, V372,C376 606 Hemoglobin subunit beta P68871 L4, V12, L15, V24, A28, L29,L32, L33, L49, V55, V61, L69, F72, L79, L82, F86, C94, L111, V114, L115,F119, V127, A130, Y131, V134, V135, A139, A141, A143 607 Hemoglobinsubunit alpha P69905 V11, A13, A14, W15, V18, A22, Y25, A27, A29, L30,M33, F34, V56, A64, A66, A70, V71, V74, M77, L81, A89, C105, L106, V108,L110, L114, A124, L126, F129, L130, V136 608 Tyrosine-protein P78324A51, L53, C55, I66, W68, I106, I111, C121, V122, F168, C170, F175, W184,A213, V215, L217, V226, C228, V230, phosphatase non-receptor L246, I250,V271, C273, V275, F278, L285, W287, C331, V333 type substrate 1 609Retinal-specific ATP- P78363 F1968, L1970, L1971, F1982 binding cassettetransporter 610 Oxidized low-density P78380 C155, C172, L179, L180,I182, I191, I195, F202, W203, M204, L206, C243, A244, I246, V251, A260,I263 lipoprotein receptor 1 611 Protein jagged-1 P78504 F35, L37, C71,F75, L79, Y132, L134, V136, A138, I161, A177, F179, I183, V185, C196,C200, C229, C262, C265, C293, C324, C333, C522, C560, C664 612 Reelin(EC 3.4.21.—) P78509 C674, C700, C1772, C1794, C2485, C2507 613ETS-related transcription P78545 V72, W75, I76, C95, L102, L110, F114,L121, I279, F303, F305, V311, A312, L329, M333, L342, F354 factor Elf-3614 C-C motif chemokine 7 P80098 C34, C35, C59, A63, V64, I65, F66, I74,A76, V83, F86 615 Protein crumbs homolog 1 P82279 C107, C221, C336,C1332 616 Mothers against P84022 V12, L15, A34, V35, L38, V39, L42, A54,I55, I65, I67, V77, Y88, C89, C109, A112, V120, C121, V122, H126, Y127,decapentaplegic homolog 3 V130, C233, I235, Y237, V244, A250, M255,V257, L271, V283, I290, V294, L296, V303, A305, C307, I313, V315, C320,I334, I342, F343, F348, V363, C370, I372, M374, F376, W380, C394, I396,L398, L400, L407 617 Disabled homolog 2 P98082 I124, A155, V168 618Basement membrane- P98160 A4204, F4206, F4214, F4219, I4230, L4232,V4234, L4242, L4243, L4244, F4259, I4260, L4262, L4264, L4269, specificheparan sulfate V4270, Y4273, L4275, A4280, V4296, A4298, I4307, V4332,I4334, C4355, V4356, L4359, L4376 proteoglycan core protein 619Polycystin-1 P98161 A290, I294, W305, F307, H323, Y325, V333, A335,L337, V352 620 Nuclear factor NF-kappa-B Q00653 L65, V80, A89, I91, V93,V96, H105, A106, H107, I119, C120, A131, L136, M150, L174, A178, V190,L192, F194, A196, p100 subunit I217, L228, V246, L248, L249, V260, F262,I287, V288, F289, V305, L307, L309, F323, Y325, Y326, H493, I496, I504,I511, V520, L531, H532, A534, V543, L546, A551, A563, M564, H565, A567,L578, H605, A607, V608, L619, A637, H639, A641, V650, L653, A675, L687,V742, L778, L782, L794, A795, L817, L818, L831, A834, L835 621 Beta-1,4N- Q00973 I281, I299, V308, V309, I310, A311, V325, M330, L342, A343,V347, Y351, F361, V382, F426, C429, V449 acetylgalactosaminyltransferase1 (EC 2.4.1.92) 622 Ankyrin-2 Q01484 F35, A39, V47, L65, A67, H69, L70,A71, A72, V80, L83, A100, L101, H102, A104, V112, V113, L116, L134,Y135, A137, A138, V145, V146, L149, A168, V169, A170, A178, L182, H197,A199, A200, A208, L212, V226, L237, H238, A240, A241, V248, A249, L252,L270, H271, V272, A273, M281, V282, L285, L303, H304, C305, A306, A307,V314, V315, L318, L336, H337, M338, A339, A340, C347, V348, L351, V371,A372, V380, L384, L468, H469, A471, A472, V480, L501, H502, I503, A504,V513, L516, L534, H535, I536, A538, V545, A546, L549, L567, H568, V569,A570, A571, A579, L582, V602, A603, V611, L615, M839, V970, V974, I991,I993, V1004, C1006, V1009, A1027, I1031, V1033, V1077, V1079, I1081,A1085, F1147, F1151, A1152, V1153, V1154, I1164, V1179, A1181, A1187,V1194, L1196, V1220, L1222, I1233, M1235, I1237, L1260, L1261, V1289,A1297, W1300, L1301, I1302, C1304, A1314, V1317, A1328, F1330, V1332,A1334, A1342, L1344, C1346, F1347, C1348, L1389, F1403, L1413, V1415,L1428, F1430, L1503, L3573, I3576, A3577, L3587, A3588, I3601, L3616,L3617, W3620, A3628, L3633, L3637, I3645, M3649 623 Collagen alpha-3Q01955 F1448, L1474, F1475, L1487, Y1521, W1522, L1523, I1545, C1548,V1550, C1551, F1583, F1586, C1604, F1613, L1614, C1616, C1622, C1662,V1664, C1665, M1666 624 Inositol polyphosphate 5- Q01968 C28, L30, L32,A33, L41, I42, I43, I56, I58, F62, C64, C82, I84, V86, F96, I98, C104,F107, L108, V111, A114, F242, phosphatase OCRL-1 (EC F243, V244, W247,V249, L258, W261, L262, I271, Y272, C273, I274, F276, L279, A285, W297,V301, M322, M323, 3.1.3.36) L324, L325, I326, F327, A328, V358, A359,V360, F362, F364, F369, C370, I371, V372, L376, I393, F399, I411, V417,W419, L420, L423, Y425, V435, L447, L453, Y479, A496, W497, C498, I501,L502, L519, V527, A529, F531, I533, V535, F572, F574, V577, I589, F599,W614, A617, L624, I632, L634, V636, V638, V643, L657, L659, L661, L669,C679, F680, L684, L687, C688, I738, L741, V742, L745, A749, L755, L765,I768, L772, V787, A788, A790, L791, F794, L795, V802, I803, C811, L812,V824, I825, L828, V835, F836, L839, F842, L843, L846, V855, I860, A861,F864, L868, F890, L891 625 Tumor necrosis factor Q02223 C24, C37, C41receptor superfamily member 17 626 Pro-neuregulin-1, Q02297 C196, C221membrane-bound isoform 627 Collagen alpha-1 Q02388 C2876, C2925 628Desmoglein-1 Q02413 C58, I70, A71, I73, V83, Y85, F100, I109, I111,V115, F123, I125, C127, A129, L143, V145, V147, L179, I218, L225, L235,V237, C255, I257, I259, I290, A305, L331, V333, L337, L347, I349, V351,I372, V374, V376, V394, A409, Y423, L433, L442, Y460, I464, I479, I481629 Desmocollin-2 Q02487 L185, L195, V201, F209, I211, I231, I233, I252,I304, L311, Y319, L321, I323, V325, C341, I343, V376, F404, L417, V419,L433, I435, V437, V458, V460, A495, I506, W517, L533, Y545, I547, A551,L563, I565, I584, C585, A633, L635, V648, I650, V652, L664, V666 630Aminoacylase-1 Q03154 Y19, L20, A34, F38, A42, V52, V60, V62, L63, H80,V83, A98, M114, L122, M141, F158 631 Trefoil factor 2 Q03403 C31, C52,C58, C69, F70, L73, C81, C101, C118, F119 632 Mevalonate kinase Q03426V8, A10, V14, H20, A21, V27, L29, V31, L33, L39, L41, V49, L51, L91,V109, A111, F112, L113, L115, Y116, L117, I119, C120, L129, L143, A147,A148, V151, C152, L153, A154, A155, A156, L157, L158, I185, A189, A206,V207, A213, L214, L233, L234, V250, I268, C275, M282, L305, V310, L315,L318, L331, C339, V353, L360, A374, V377, I379 633 Complement factor H-Q03591 Y53, I70, C87, V110, I127, C129, I249, C251, C266, A296, C317related protein 1 634 1,4-alpha-glucan-branching Q04446 L31, L38, F45,I59, F69, C88, A92, A95, V98, L100, V136, L142, V144, V145, I146, I157,A161, V164, L197, I199, Y200, enzyme (EC 2.4.1.18) H203, V204, I206,Y216, F219, V223, L224, I227, L230, Y232, C234, I235, L237, M238, I240,M241, H243, F249, I253, F256, F257, A258, A259, L269, L272, V273, A276,I281, V283, L284, L285, V287, V288, H289, A292, L300, F303, Y310, F311,H319, I334, L335, F337, L338, L339, I342, W345, L346, Y349, F351, F354,F356, V359, M362, L363, Y364, A389, L390, Y392, L393, M394, L395, A396,L399, V400, I410, A411, M417, A419, L420, I439, W443, L446, W455, M457,I460, L464, I474, A475, Y476, A477, H480, L490, A491, M503, I513, I517,L519, H520, M522, I523, L525, I526, H528, L530, Y535, L536, F538, M539,F543, L549, F551, A563, L580, F583, M587, L590, W596, L597, I613, I614,A615, F616, L621, L622, F623, I624, F625, V638, F646, L650, A654, L683,V685, I687, V691, A692, L693, I694, L695, V698 635 Glutamatecarboxypeptidase Q04609 F61, I70, L74, F77, L83, A84, A93, V108, L110,Y113, V115, L117, I128, I130, V158, F161, A163, F164, L174, V175, 2 (EC3.4.17.21) Y176, V177, A180, L188, C196, I200, V201, I202, A203, V214,A217, V225, I226, L227, Y228, Y234, A236, V253, I258, L259, A264, L268,A274, V287, V294, I297, A302, L305, L306, M309, A313, W319, V329, V342,M344, I346, I355, V358, L362, V372, I373, L374, H377, V382, F383, I386,A393, V394, H396, I398, V399, F402, L405, I416, L417, F418, A419, W421,A423, F426, L428, L429, A435, L442, V447, A448, Y449, I450, A452, I456,Y460, L462, V464, C466, L469, M470, V474, L477, W93, W497, L515, F521,V523, F524, F525, I530, A531, A535, Y537, Y549, L551, H553, V555, L561,V562, F565, F570, H573, V576, A577, V579, M583, V584, L587, A588, C597,Y600, A601, V603, L604, Y607, A608, I611, V627, L632, V636, F639, A643,F646, L661, M664, L668, M669, L671, F675, L679, F686, Y687, H689, I691,Y692, A693, F705, I708, L712, V728, I732, Y733, A735, A736, V739, A742,A743, L746 636 Copper-transporting ATPase Q04656 V10, I12, V14, M17,C22, V23, I26, I30, A48, I50, Y52, L62, I66, L173, M175, V177, I189,I193, A211, I213, Y215, V222, 1 (EC 3.6.3.54) M225, I229, F234, F281,I283, V292, I295, L299, A317, V319, L331, I335, I381, I383, M386, C391,V392, I395, I399, V419, Y421, L431, I435, C490, I492, V503, I506, L510,I516, L520, A528, V530, Y532, I542, I546, L566, L568, V570, I582, L586,C595, A604, I606, Y608, I618, I619, I622, A629, V837 637 Neurogeniclocus notch Q04721 C315, C491, C642, C1184, C1443, C1455, C1484, L1490,C1509, C1522, W1529, L1547, I1549, V1551, L1558, F1565, homolog protein2 L1573, V1623, L1625, I1627, C1632, F1640, A1646, A1647, L1649, L1650,A1651 638 Activin receptor type-1 (EC Q04771 V402, L411, V424, V447,L470, L473, W478, L489, L495, I498 2.7.11.30) 639 Acetylcholine receptorQ04844 V49, I51, L53, V55, I61, V74, I76, I78, W80, V105, W106, V111,L112, A123, V128, V130, V136, W138, A142, C148, subunit epsilon V150,W159, F166, V176, F178, V230 640 Focal adhesion kinase 1 Q05397 V39,H58, V64, I67, I68, V72, C82, L87, L124, Y128, F137, F146, F147, Y148,A160, A168, L171, C173, L174, L188, Y194, L203, F207, A217, F228, L241,F243, F244, L247, F258, L272, A273, I274, I280, A294, I302, L316, L318,A323, V329, A331, A337, M340, A341, L343, I344, C348, A369, I373, V436,V451, A452, I453, C459, F468, A472, M475, I483, V489, I490, V495, I497,I498, M499, C502, L507, L511, I524, Y526, A527, L530, A533, L534, L537,I547, A548, A549, V552, L553, V554, V560, L562, F565, L567, A579, M589,A590, V605, M607, F608, C611, M612, I615, V631, I635, L651, L654, M655,C658, W659, F669, L672, L676, V928, L931, V932, M938, I942, Y950, V957,L961, L964, V968, I983, L990, L997, A1004, M1020, A1024, L1027, A1028,A1031, L1034, I1038, A1041 641 External core antigen/ Q05495 Y35, F38,L44, L45, F53, A63, H81, L84, A87, A98, V118, L129, L130, F132, H133,V144, L148 genotype F2 (isolate Brazil/w4B) (HBV-F) 642 Glutamatereceptor Q05586 A71, V107, Y109, A111, Y158, I163, A236, L269, A279,A284, I301, V309, I314, I400, V401, F408, V409, C436, C454, ionotropic,NMDA 1 C455, F458, C459, I460, L462, L463, L466, V479, M501, M502, L505,A510, M512, I513, V514, A515, L517, L538, I540, L541, V542, L672, Y681,A682, V689, F693, M702, Y703, M706, A717, V721, L726, A728, F729, I730,W731, V735, L736, F738, L746, F758, I760, M762, V772, I776 643Tyrosine-protein Q06124 W6, F7, H8, A16, L19, L20, F29, L30, A31, L43,V45, I54, I56, Y63, L65, F71, A72, L74, A75, L77, V78, Y81, L88, I96,phosphatase non-receptor L98, L102, A122, L125, L126, F135, L136, V137,F147, V148, L149, V151, I172, L190, L193, V194, V209, L210, L212, type11 (EC 3.1.3.48) L216, I221, A223, I226, V230, L233, F247, L254, I282,L283, F285, V290, Y304, A307, I309, I310, Y327, I328, A329, C333, V338,F341, W342, M344, V345, V352, I353, V354, M355, C367, Y370, W371, Y380,M383, V385, L401, L403, V419, Y422, H423, F424, W427, V439, F442, L443,V446, I453, V459, V460, V461, H462, C463, A465, I467, G468, F473, I474,V475, I476, I478, L479, I480, I482, I483, V488, I492, V494, I498, V501,M508, V509, Y515, F517, I518, Y519, A521, V522, I526 644Tyrosine-protein kinase Q06187 L31, V427, I429, I432, F442, A446, M449,M450, L452, L457, V458, V463, C464, I470, I472, I473, L482, L486, L498,BTK (EC 2.7.10.2) M501, C502, V505, C506, A508, M509, L512, H519, L522,A523, A524, C527, V529, V535, V537, F540, L542, V568, I580, W581, F583,V585, L586, M587, W588, I590, Y591, Y598, I610, L616, A622, V626, M630,C633, W634, F644, L647, I651 645 Acetylcholine receptor Q07001 V52, V54,L56, L58, I79, W83, V108, W109, L115, V131, V133, V139, W141, A145,C151, I153, W162, F169, I179, subunit delta L181, I253, V330 646 Earlyactivation antigen Q07108 Y97, A109, C113, L120, A121, I123, L132, W142,V143, L145, C173, V174, L176, I193, C194 CD69 647 Neuraminidase (ECQ07599 M83, A92, F95, I104, I112, V114, I115, F119, V120, F130, F131,L132, L156, V159, A174, A176, W177, A179, A181, 3.2.1.18)/strain C182,M189, V191, V193, A200, V201, A202, I204, V214, L222, C231, I232, C236,Y237, W238, V239, M240, A249, A/Duck/Ukraine/1/1963 Y251, I253, A256,I261, H273, I274, C277, C279, Y280, V286, C288, V289, C290, L302, I304,L315, C316, A317, I319, H3N8 V346, F349, F351, V357, W358, M359, I363,F371, I373, L374, I376, V393, V394, L397, F406, L418, C421, F422, W423,V424, M426, W437, I443, V444, M445 648 Prolow-density lipoprotein Q07954F859, C861, C879, C895, F900, C902, I908, C914, C920, C936, C943, C955,C961, F982, C984, C1002, F1020, C1022, receptor-related protein 1 C1040,F1067, C1069, C1088, F1110, C1112, C1131, C1152, V1158, L1160, C1172,C2679, C2696, C2715, F2739, C2741, C2759, C2781, V2786, V2788, L2793,C2794, C2800, A2804, C2812, C2818, C2837, F2863, C2865, C2884, C2912,C2930, F3379, C3381, C3399, C3453, F3458, C3460, I3467, C3473, C3479,C3494, F3499, C3501, I3508, C3514, C3520, C3536, C3543, V3549, C3555,C3561, C3575, F3580, C3582, I3588, C3594, C3600, C3613, C3620, C3632,F3659, C3661, C3679, C3703, C3749, C3767 649 Hemagglutinin [CleavedQ07FI5 V7, I20, C21, I22, A26, V33, V36, V43, L49, L50, L58, C59, L61,L67, L69, C72, V74, A75, W77, I78, L79, C84, L87, into: HemagglutininHA1 W93, Y95, I96, V97, Y108, L118, L122, V125, F128, F134, A150, C152,H154, L164, L165, W166, L167, L173, L177, chain; Hemagglutinin HA2 V189,L190, V191, L192, W193, V195, H196, H197, Y208, Y214, V215, V217, V218,I243, Y245, Y246, L249, L250, I256, chain]/strain F258, A260, L264,I265, A266, Y269, A270, F271, A272, L273, F277, I281, I282, C291, C295,A301, I302, H312, I316, A/China: Nanchang/11/1996 V323, L328, M330,V331, A348, M360, Y365, A387, I388, A439, L451, V458, L461, V465, L469,C480, H485, C487, H1N1 C491, M492 650 Hepatocyte growth factor Q08048F43, C71, A72, C75, C85, A87, F88, V89, C97, W99, L119, W153, C178,C190, F191, C207, C233, W236, C261, C272, C284 651 Interleukin-10receptor Q08334 L38, A54, L57, C74, F76, L87, V89, A91, V108, L127,M145, V156, V189, V191, L195, V208 subunit beta 652 Epithelial discoidindomain- Q08345 M37, A72, W73, L87, V89, V97, V100, I141, M159, A161,V164, F166, L178, V180, L182, L191, Y194, A196, V208, containingreceptor 1 L210, L231, F241, Y255, V256, W258, V268, M270, F274, F280,M283, V285, C287, A295, V301, C303, F305, V336, L338, A343, L346, C348,F350, L357, L358, F359 653 Tyrosine-protein kinase Q08881 I358, V388,I390, I393, A397, F403, A407, L418, V419, V424, C432, V434, L443, L447,L459, M462, C463, V466, ITK/TSK (EC 2.7.10.2) C467, M470, L473, H480,L483, A484, A485, C488, V490, I496, V498, F501, V522, V541, W542, F544,V546, L547, M548, W549, V551, V567, I571, A583, I590, M591, C594, W595,F605, L608, L612 654 ATP-binding cassette sub- Q09428 I701, I703, L708,M710, I711, V712, C717, L722, L723 family C member 8 655 Potassiumvoltage-gated Q09470 A347 channel subfamily A member 1 656 Neuraminidase(EC Q0A2R1 L86, V93, A104, I105, I113, V115, Y120, V121, C123, M130,Y131, A132, L133, L157, I158, C175, V176, C183, M190, 3.2.1.18)/strainI192, C193, V194, A201, A203, V205, Y207, A219, L223, C230, V231, C232,A238, V239, V240, M241, V254, M255, A/Chicken/Victoria/1/1985 Y256,F257, I275, C278, C280, Y281, I287, C289, V290, C291, A298, I302, I303,I305, Y316, V317, C318, V321, L322, H7N7 V349, F352, F354, W361, L362,F374, M376, L377, I379, A382, I396, V397, F409, I410, Y420, F424, Y425,V426, L428, V439, L446, I447, A448, L449, A465, I467 657 Hemagglutinin[Cleaved Q0A448 A26, V50, L58, C59, M60, Y65, L68, C71, V74, M76, I78,C83, W91, L94, I95, I101, C104, L115, I119, I125, M128, into:Hemagglutinin HA1 I138, C147, Y156, L159, L162, Y178, H186, L187, I188,I189, W190, I192, H193, Y205, I212, V214, I240, F242, V247, chain;Hemagglutinin HA2 I253, F255, H257, L261, I262, A263, V267, L270, I277,C287, C291, F292, A345, Y362, A384, L458, L466, H482, C484,chain]/strain C488, A506 A/Duck/Germany/1949 H10N7 658 Endogenousretrovirus group Q0ED31 A54, H65, A69, M94, M99, V100, M103, L110, W111,L115, V119, V154, I165, Y193, C220, V226, I227, L228, C230, K member13-1 Env C241, V244, I253, L261, I272, I286, I287, V288, H289, L290,V294, I296, C298, I327, A330, C332, I334, W339, L343, polyprotein V346,L350, I359, I360, F361, H374, C378, F382, F383, Y384, C385, L390, F391,L410, C412, I414, I417, I418, A427, M428, I437, I443, I446, L447, L448,F462, W473, L477, Y480, V483, I485, V499, I542, L549, A552, I553, A555,L559, L560, V564, I567, L570, V574 659 Carcinoembryonic antigen- Q0Z7S6L36, A45, V51, L52, L53, V55, Y65, W67, I79, I80, A105, L107, M109,V112, Y120, L122, V124, F138 related cell adhesion molecule 8 660 Spikeglycoprotein/isolate Q0ZME7 F67, F103, V106, V125, I137, V138, A150,C151, C156, V162, L198, H201, F209, A211, Y212, A214, F222, Y236, N5(HCoV-HKU1) V237, M238, C242, Y256, Y266, L267, L268, A279, C282, L333,C352, F383, V388, F391, A392, L409, C423, Y427, Y458, A477, I588, F589,L624, F633, A680, C719, C743, V765, I943, A1025, A1070, A1084, L1085,L1098, A1103, A1106, F1143, I1144 661 NS3 protease Q0ZNA6 C16, V33, V35,V36, L44, A45, C47, V48, V51, C52, W53, V55, A59, L64, I71, L82, V83,W85, L94, L104, L106, V107, V113, I114, V116, V132, L135, L143, L144,C145, A150, V151, I153, F154, A164, A166, V167, F169, V170, V172, M175662 Calcium-activated potassium Q12791 F815, L907, M922, C923, C943,A946, F955, L1026, A1037, I1060, A1104 channel subunit alpha-1 663Potassium voltage-gated Q12809 I30, A32, C44, F48, C49, L51, C52, A57,V59, C64, C66, A78, I82, A83, I96, A97, F98, C105, V110, V112, L127,A763, channel subfamily H A778, I782, I787, I804, F805, V822, A824,L830, V841 member 2 664 Glutamate receptor Q12879 M112, I116, A136,M162, F170, F177, V187, V191, V203, V217, L248, L260, V292, L307, I408,V409, F416, V417, ionotropic, NMDA 2A V419, C436, V440, C455, C456,F459, C460, I461, I463, L464, L467, L479, W493, M496, I497, V500, A505,V506, M507, A508, V509, L512, V522, V529, V535, M536, V537, V662, L665,F670, F682, I694, M701, M705, A716, A727, F728, I729, A732, A733, V734,L735, Y761, I763, A764, L765, I775, A778, L779, F782, M788, L791, V807665 Unconventional myosin-Ie Q12965 A1058, F1072, I1078, F1100 666Glutamate receptor Q13002 L36, F38, I41, A56, F57, A60, V61, I64, L71,I83, A91, A95, L99, V103, A104, A105, I106, F107, A115, V118, C122,V127, ionotropic, kainate 2 H129, I130, V147, L149, F153, L156, A159,I160, L163, V164, V172, V174, V175, L185, L188, A191, L197, L204, A211,L215, M218, V226, I227, F228, A235, A236, I238, L239, A242, M247, Y254,I255, F256, L259, L261, L264, M276, F279, L282, W296, M316, A320, A321,L322, M323, A326, V327, V329, V330, A333, M340, L345, W353, F359, I363,A366, I375, F387, L389, V391, I392, W405, L433, I434, V435, Y443, V444,F446, L453, F459, Y462, C463, I464, L466, L467, L470, I480, A490, M501,V502, L505, A510, L512, A513, V514, A515, L517, A518, I527, F533, L536,I538, I540, L541, Y542, L674, A675, I680, Y682, A684, M691, F694, M705,M709, V716, V718, V728, Y733, A734, F735, L736, M737, I742, L752, Y764,V766, I778, A781, I782, L785, L791, M794, W799 667 T-lymphoma invasionand Q13009 M40, A441, L446, V454, V467, L469, L474, F476, V497, I501,V502, V514, F515, C516, L517, A524, F527, L535, W538,metastasis-inducing protein I542, H543, A545, C546, A547, A551, L563,M616, C623, Y624, L639, M651, F662, A664, V666, A667, A668, I848, 1Y858, L873, A884, I895, I898, A903, L906, L920, V924 668 Secretoryphospholipase A2 Q13018 F182, C204, C219 receptor 669Platelet-activating factor Q13093 I56, C67, M71, F80, L81, Y84, Y85,W97, I98, Y103, L111, L116, M117, L124, F125, A132, Y144, L146, V147,V148, acetylhydrolase H151, F156, I165, A168, F172, I173, A175, H179,A184, A186, Y189, V222, A226, C229, A232, L233, I239, I267, A268, V269,I270, A277, V279, I280, L283, F289, C291, I293, A294, A297, M299, V306,I310, L314, F315, F316, I317, I328, M331, C334, I344, F354, F357, A380,A387, L389, A390, F391, L392, F402, I422 670 S-methyl-5′-thioadenosineQ13126 I12, I14, I15, L26, L45, C55, V56, L57, L58, A76, I78, A80, L81,H88, V89, I90, V91, C95, L98, I107, V108, I109, I110, phosphorylase (EC2.4.2.28) A132, L152, A156, M169, V170, F186, A191, V193, V199, V202,L204, A205, I210, C211, Y212, A213, I215, A216, M217, A218, L250, I255,I258 671 Glutamate receptor Q13224 I35, I37, A38, V39, I40, V65, I81,I85, V97, V98, F99, A100, I108, A109, I111, L112, I115, A117, I123,L124, I126, A135, ionotropic, NMDA 2B F146, A154, V156, M157, I160,M161, F169, I171, V172, F176, F182, I186, I190, V202, L205, I216, L220,L223, I228, L229, L230, Y231, C232, A237, I240, F241, A244, L249, W256,I257, V258, L261, V262, A263, L277, I278, V280, V293, I299, I300, A303,A304, M307, L308, I329, L335, L339, V342, V363, I364, I365, L367, V376,I408, V409, F416, V417, V419, C436, I440, C456, C457, F460, C461, I462,I464, L465, I468, L480, W494, M497, I498, V501, A506, Y507, M508, A509,V510, L513, V523, I530, V536, M537, V538, V663, L666, F671, F683, I695,M702, M706, A717, A728, F729, I730, A733, A734, V735, L736, Y762, I764,A765, I766, V776, A779, I780, L783, M789, L792, V808 672Chitotriosidase-1 (EC Q13231 L24, V25, C26, Y27, F28, A32, A39, F41,L46, L50, C51, L54, I55, Y56, A57, F58, A59, M61, Y77, F80, L90, L93,L94, A95, 3.2.1.14) I96, F101, F106, M109, V110, F119, V120, A123, L127,F132, L135, L137, W139, F155, L158, V159, L162, F166, L178, L179, L180,A182, A183, V184, A186, V191, V197, I200, A201, L204, F206, V207, L209,A211, H224, L228, V243, A246, V247, W250, L260, I261, L262, M264, F271,V281, A283, A302, Y304, V306, V322, Y324, I325, W331, V332, F334, F340,V344, L347, A355, M356, V357, A359, L360, F365, Y375, L377, I378, L381,C420 673 Noggin Q13253 L66, V173, C184, V202, L203 674 Butyrophilinsubfamily 1 Q13410 A40, A46, L48, C50, A58, L63, W65, A73, V74, Y91,L109, I111, V114, Y122, C124, F126, L136, V137, L139, I208, member A1V364, V379, F452, F460 675 Mesothelin Q13421 I311, L315, I316, L323,C326, V327, L332 676 Alpha-1-syntrophin Q13424 L13, V31, L33, L40, V42,V88, V90, I112, I114, A122, A123, L129, A134, I135, V138, L143, A151,V162, V163, L164, V166, M215, L236, I238, A241, L247, L249, A251, A257,I264 677 Interleukin-18 receptor 1 Q13478 I28, V31, L38, H40, W56, V82,L83, F85, V88, Y96, F98, W107, L109, F136, C140, L154, A175, C185, H187,L189, C237, A239, L241, A278, L282, I284, C298, V300, L313 678Myotubularin Q13496 I185, L321, Y329, I350, L385, L388, L393, F438,A455, F475, L479, I539 679 Sequestosome-1 Q13501 A8, L10, L47, V51, F55,A65, F77, A86, I97, I99, L394, M401, L413, L417, A427, I431 680Polycystin-2 Q13563 L736, L745, L770 681 Myotubularin-related proteinQ13614 A88, V91, L105, V107, L112, F114, A127, L129, V131, I132, L151,I158, L161, F163, A164, I175, L179, F184, A194, 2 W225, I227, C237,Y240, L244, V245, V246, I250, L255, V258, I267, V269, L270, A279, I281,C284, Y302, L303, A305, I306, I316, I318, F319, A321, A327, I353, L363,L366, Y371, W388, I392, I395, L396, A399, I402, A403, V406, V413, V414,V415, H416, A425, L427, L430, A431, M432, L433, M434, L435, Y439, I442,F445, V447, L448, V449, W453, F456, H458, F460, H466, A472, F480, L481,F483, I484, C486, V487, M490, A497, F498, F504, L505, I508, L509, F517,F520, L521, L533, L540, W541, I544, F551, L564, W576, Y579, Y580, I581682 Cullin-4B Q13620 L220, A223, V224, A226, L240, A243, V244, L256,L260, C264, L286, I289, M300, I303, I306, F307, L310, V315, I324, M327,F332, I336, I337, V342, I347, I350, L351, I354, L368, L371, L372, M374,L375, L378, Y381, F385, F389, Y397, V410, Y413, L414, V417, L421, L428,L440, V444, L448, L449, I456, L457, L461, L464, L465, L473, L476, L479,F480, L490, W494, I498, I505, V506, M515, V516, L519, L520, V526, I529,I532, C533, F534, F540, A543, M544, A547, F548, F551, I552, A560, L562,I563, A564, V567, L571, L587, I590, I593, F594, I597, V602, F603, F606,Y607, L611, A612, M629, L633, L645, M648, F708, F711, A734, L743, V745,F748, V752, I767, L778, L782, L785, A786, F808, I823, I850, A853, I854,M858, L869, V873, L886, I890, L893, M899, Y909 683 Interleukin-10receptor Q13651 A36, F39, H41, L43, V59, A60, L83, A98, V100, A102,F118, V123, L125, V130, Y157, F161, Y167, I169, V203, V205, subunitalpha V209 684 Voltage-dependent L-type Q13698 A603, V610, V1010, A1023,A1312, L1329 calcium channel subunit alpha-1S 685 Laminin subunitgamma-2 Q13753 C550, C570 686 Ectonucleotide Q13822 C59, C76, C80, F90,C94, C118, C120, C124, C130, C131, W144, L166, I167, F169, V171, F174,Y178, M186, I189, L192, pyrophosphatase/phosphodi- M202, Y206, Y222,H226, I228, V229, M233, F242, W254, L260, A264, I280, I286, I289, L295,V303, Y304, F306, esterase family member 2 M325, L329, V336, L339, M340,L343, C351, V352, I355, F356, V357, H360, M362, V365, C367, F372, L373,L390, I393, I409, L412, Y424, I444, H445, L446, L447, V454, F477, M484,F488, V489, F495, V501, F504, I507, L509, Y510, M513, C514, L517, L534,M544, A603, V604, Y610, L613, F618, Y622, M628, W631, Y634, C652, V653,V659, A669, L681, F682, A692, A696, F697, V699, M702, V703, M705, A708,V712, W713, F716, V719, L720, V721, A725, V731, V733, I738, F739, V757,I762, V764, Y768, Y769, I771, I772, I795, L796, V816, M820, H823, A825,V827, I830, L833, L836, F838, I849, L850, L852 687 Plakophilin-1 Q13835A250, L254, A266, I269, C273, A279, V283, L292, V293, V303, A306, A307,A308, A310, L311, L314, V315, L338, I346, L350, L354, L367, A371, L372,L375, A376, V379, I380, V402, F403, A406, C409, L410, L434, M444, L450,I451, L454, M455, V458, V472, C475, M476, V478, L479, L482, L486, L543,A548, I549, Y552, L555, A567, C568, A569, A571, L572, L575, M582, M586,I590, L597, I600, V611, A616, L618, L619, M622, L628, M632, V636, F637,I657, A661, V665, L668, A670, A700, A704 688 Bone morphogenetic proteinQ13873 L492 receptor type-2 689 Voltage-dependent L-type Q13936 I702,V1131, A1453, M1470 calcium channel subunit alpha-1C 690 Coactosin-likeprotein Q14019 C10, A12, A13, Y14, V17, W26, V27, F29, I36, F48, C52,L58, F59, A60, F61, V62, F64, A77, L78, I79, W81, I82, V101, V104, V105,I114, L120, I125, L129 691 Heterogeneous nuclear Q14103 M99, I101, L104,L113, F117, L130, V143, V154, H160, I167, I184, V186, I198, F202, C226,I228, F230, V236, I239, ribonucleoprotein D0 H245, V247, I254 692Lysosome membrane protein Q14108 V42, L43, F64, F66, F67, V69, I75, Y89,F102, I109, A111, I133, L136, I138, V140, V143, I156, L160, L167, V173,L177, 2 I184, I188, L201, Y213, I228, C245, F256, F269, F273, C274,V287, A292, F293, Y295, A299, I301, L302, V323, V326, M337, F342, F349,V350, I353, I369, I376, L377, A379, I387, V389, F395, V396, F406, V408,M409, V415, A422 693 Low-density lipoprotein Q14114 F52, C54, C72, C93,H97, I99, C111, C134, V142, C154, A158, F172, C174, L180, C192, F211,C213, A220, C234, C285, receptor-related protein 8 C340, I350, C351,C362, C374, L424, F426, I435, L437, I446, A454, A503, Y512, L570, V601,I634, A635, I651, C700 694 Dihydropyrimidinase Q14117 L7, L8, I9, V14,V15, A23, V25, V27, V32, L35, A54, V59, L60, I64, H67, H69, M70, M75,I80, F83, A89, A90, L91, M97, I98, I99, F101, A102, L110, I111, A113,W117, A121, V125, C126, C127, Y129, L131, H132, V133, A134, V135, V142,M146, L149, V150, V155, F158, M160, M162, A163, Y168, V170, L175, A178,F179, C182, I185, A187, I188, A189, V191, H192, A193, H217, A229, A233,I234, I236, A237, L244, Y245, I246, V247, H248, V249, M250, A254, A255,I258, A261, V268, I273, A274, A275, L277, Y284, A292, A293, H295, V296,M297, L301, L311, M312, L314, L315, L320, C328, F330, F342, I345, V349,V352, M356, V358, I359, W360, V364, F374, V375, V377, A382, A383, I385,F386, I395, A401, I403, V404, I405, W406, I414, V423, F428, C433, V439,I441, V447, F462, I463, A469, I472, Y473, I476 695 Desmoglein-2 Q14126L58, L64, I85, Y87, I101, F102, L111, V113, L117, F125, L127, A131,L145, I147, I181, V210, I220, L227, L237, V239, A241, A256, V258, I260,I293, V295, A308, V334, L336, V340, V352, I375, V377, F413, A415, Y428,W437, I438, I447, Y465, V467, I469, A471, V485, I487, V515, W544, V554,L556, I568, F570, I572, L586, L588 696 Cytoplasmic dynein 1 heavy Q14204L2837, V2838, M2953, L2956, I2993, L3115, V3352, V3472, L3645, I3669,V3780, V3790, I3811, L3856, L3947, V4031, chain 1 L4158, L4331, F4482,L4514 697 Filamin-C Q14315 F42, C46, L50, L57, L60, L64, L70, I71, L73,L74, V100, V102, A103, L104, F106, L107, I122, I130, L131, L133, I134,L137, I138, I143, L165, I169, V173, F181, W185, A190, L191, A193, L194,V195, A199, C203, A218, A221, M222, A225, L229, V231, V234, I235, I240,V250, M251, Y253, L254, A278, A296, V300, A305, V312, V338, H348, V350,V352, F354, I359, V366, A590, F592, V593, V594, C626, V628, Y630, Y638,V640, V642, A656, C665, A688, I692, A697, C728, I740, I741, I742, V756,V758, V1065, F1083, I1085, A1090, V1119, Y1121, Y1129, I1131, I1133,I1140, A1147, I1149, V1158, A1160, V1178, A1183, I1192, I1214, Y1216,Y1224, I1226, I1228, Y1230, V1242, V1253, V1265, F1273, V1275, V1292,Y1312, V1314, Y1316, H1324, V1326, V1328, V1342, V1353, F1371, V1373,A1378, V1407, Y1409, Y1417, V1419, I1421, I1428, V1435, V1437, V1446,V1457, V1467, A1472, V1481, V1503, V1515, V1517, Y1519, V1524, I1531,V1533, V1542, I1554, A1556, F1562, I1564, A1566, A1569, I1578, V1600,Y1602, Y1610, I1612, I1614, Y1616, I1621, I1628, A1630, A1636, C1639,I1666, V1668, A1673, V1678, V1682, I1704, A1708, Y1714, I1716, I1718,I1725, V1732, A1734, V1793, V1802, I1822, V1824, H1834, M1836, I1838,I1845, V1862, F1880, I1882, V1916, Y1918, Y1926, I1928, V1930, F1932,I1937, A1944, I1946, I2003, F2005, H2013, V2015, V2017, V2033, A2041,V2044, V2064, V2098, Y2100, Y2108, I2110, I2112, F2114, V2126, V2128,V2254, Y2274, V2276, H2286, V2288, V2290, V2306, V2317, F2335, I2337,V2371, Y2373, V2375, Y2381, V2383, I2385, I2392, V2399, V2401, A2402,A2408, L2411, L2421, V2431, L2433, A2436, I2440, V2444, I2466, H2476,I2478, V2480, F2482, I2494, V2508, L2515, F2526, V2528, A2533, V2561,Y2563, A2567, Y2571, I2573, I2575, Y2577, I2583, A2590, A2635, V2638,A2648, V2658, C2660, A2663, V2694, Y2696, V2698, L2706, V2708, W2710,V2715, V2722 698 UDP-glucose 4-epimerase Q14376 V5, L6, V7, H17, V19,L20, L22, V30, V31, I32, L49, V52, V60, A72, L73, L76, F82, A84, V85,I86, H87, Y104, L115, (EC 5.1.3.2) I118, M119, V124, L127, V128, F129,A133, V135, Y136, L144, H148, I164, I168, W178, A180, V181, L182, L183,A191, I197, M209, V212, V225, I242, H243, V244, L247, A248, H251, A253,A254, L255, L258, Y267, L269, M280, V281, A283, M284, A309, L313, A314,L318, W320, M329, C330 699 Semaphorin-3A Q14563 I110, L308, V373, I451,V475, L476, L494, L529 700 Inositol 1,4,5-trisphosphate Q14571 L9, I11,V15, A19, I27, C37, V38, V39, Y66, V115, L123, H125, L132, A146, F161,I176, L193, V209, W218, L242, H244, receptor type 2 C253, L264, A280,W282, I284, H307, A315, A316, L354, F367, H391, V398, I417, F429, A448,L452, L476, V483, I514, V518, C556, H562 701 Inositol1,4,5-trisphosphate Q14573 L8, I10, V14, A18, I26, C36, V37, V38, Y65,V116, L124, H126, L133, A147, L162, V177, L194, V210, W219, L243,receptor type 3 H245, C254, L265, A281, W283, V285, H308, A316, A317,L354, F367, H391, I398, L417, F429, A448, L452, L476, V483, I514, V518,C556, H562 702 ATP-sensitive inward Q14654 L149, L233, L255, L287rectifier potassium channel 11 703 Metabotropic glutamate Q14833 L83,L86, A328, V341, L353, A363 receptor 4 704 Transmembrane Q14956 L274,I279, W283, F285, V293, V299, Y303, F309, A317 glycoprotein NMB 705Importin subunit beta-1 Q14974 I6, L7, A21, L25, L40, L44, A53, A56,A57, L59, I61, L65, W80, V91, V95, A109, C112, V113, A114, I116, A117,L129, L133, V137, L151, A153, I157, I161, L166, I173, A176, I177, I178,V190, A194, A197, L198, L202, F209, I218, M219, V221, V222, V233, A236,A237, L241, I244, M245, M252, L260, A267, M268, V275, A276, I280, F282,W283, V286, C287, A300, A301, A315, A318, L319, L322, V323, L326, L330,C345, A347, A348, C351, L352, L355, A356, I363, V367, A385, A386, V387,A389, C392, I393, L394, L402, V406, L413, V424, A428, A429, V432, I435,C436, L439, A442, A443, L452, C455, L456, L460, A467, V470, C471, A473,F474, L477, A478, A481, L499, F503, I506, V507, L510, L524, A528, Y529,L532, M533, I535, V536, A540, C543, A546, V547, I554, L558, V561, L562,L584, C585, L588, V591, L592, V595, A600, I603, V607, M608, L611, M614,F615, V624, A628, L629, A631, V632, L635, V636, L639, F643, M647, F650,L658, V666, C667, A670, V671, L673, V674, L677, C678, L681, M693, L696,V709, I713, L714, V716, F717, I720, A721, F728, V735, L736, L739, A742,L758, C765, L766, A768, Y769, I772, V773, L776, V787, V790, V794, I797,L798, F800, I801, I804, V814, V815, A816, A818, A819, L821, I822, L825,A828, V833, V837, I843, L846, L847, A858, L861, A862, A865 706 Arf-GAPwith coiled-coil, Q15027 V411, C421, C423, A431, V437, L439, C443, H447,L472, M473, I481, I484, I510, L575, M588, A591, A593, A614, ANK repeatand PH domain- A622, C623, L626, A647, L655, A656, F659, A680, I688,L691, L713 containing protein 1 707 Lysine--tRNA ligase (EC Q15046 I84,L105, F108, V128, I132, Y145, L147, L154, V156, A158, L176, I182, V184,I198, I199, L232, V240, I250, I254, 6.1.1.6) L258, F263, I266, I274,I298, H304, V308, V315, Y316, I318, C338, F340, L350, M357, V358, M361,V362, V385, F387, F391, I394, M396, V397, L400, F414, L423, C427, L443,L444, L447, V448, L452, C456, F461, I462, H465, L472, A473, F486, L488,F489, V490, M491, C496, A498, L502, L511, F533, C534, A545, W547, M549,I551, V554, A555, M556, F557, V567 708 Advanced glycosylation end Q15109L36, W51, L53, W72, A76, L84, L86, V89, F97, C99, A101, V115, V117,L133, V141, C144, W157, L192, C208, F210, product-specific receptorL214, V238, L257, W271, C301 709 Programmed cell death Q15116 A50, F52,C54, F56, L65, W67, A80, A81, F106, M108, V110, A113, Y121, C123, A125,A140, L142, V144 protein 1 710 Plectin Q15149 F185, W188, V189, L193,A196, L203, L207, L213, I214, L216, L217, V240, A243, L244, L247, L254,I262, A263, L271, L273, I274, I277, I278, I283, I286, L301, W304, V309,C317, F320, W324, L329, F330, A332, I333, I334, L341, V347, L353, L356,A359, F360, A363, V369, L372, L373, V378, I388, I389, Y391, V392, L395,Y396, Y421, V425, L428, M432, I451, L483, V503, L510, L521, C545, L549,A552, L556, V575, L579, A582, L589, V593, L596, V611, L618, L662, L665,W668, V669, V688, I702, F705, A712, Y727, L731, L734, L741, L752, L755,F758, V759, A762, L769, L798, A826, V830, L837, M844, L847, C850, I851,H854, F864, A871, L875, L918, L921, A925, L931, L946, C950, V988, V991,C992, F993, V995, A1002, V1006, L1009, A4418, I4420, I4431, A4434,L4448, L4449, A4453, C4454, I4458, I4459, V4469, A4472, I4486, A4489,A4492, A4507, A4508, A4510, A4520, F4524, L4525, A4548, L4562, A4567,L4572, A4586, L4600, A4603 711 Nectin-1 Q15223 L49, C51, V65, W67, V78,A79, Y93, I109, L111, Y122, C124, F126, L138, V142, L168, A170, C172,L213, A219, L224, C226, I227, V228, L239, V243, L267, C269, L300, F302,Y314, C316, A318 712 Receptor-type tyrosine- Q15262 Y77, M78, V80, A91,L93, L95, H104, F108, L123, I125, V127, I138, A152, L154, A155, V156,Y164, V166, F168, A170, protein phosphatase kappa I180, A181, I182,F214, C216, L230, A253, F255, Y268, C270, V271, V280, A284, L308, I310,L312, V328, I361, L365, I406, V408, C420, I427, V454, V463, L465, M467,L469, I507, L509, Y524, I526, F558, Y567, F569, I571, A573 713 Receptortyrosine-protein Q15303 Y53, C56, V58, V59, L63, I65, I68, L77, V80,V83, V87, L88, V89, A90, F94, L97, L99, L102, I104, I105, A116, A118,kinase erbB-4 (EC 2.7.10.1) I119, L131, L134, L136, L139, I142, V147,V149, A158, I166, V167, C197, C234, A235, A248, C258, V298, C334, I337,V348, I353, F356, C359, I362, L366, F368, L389, F392, V395, I398, L402,I404, F414, V416, F417, L420, I423, L434, I436, I442, L445, F447, L450,I453, I458, I460, L466, C467, L477, C496, C507, C512, W513, C532, V748,I750, A769, A773, M775, L780, V786, C787, V795, L804, V808, L820, L821,W823, C824, I827, A828, M831, L834, H841, L844, A845, A846, V849, V851,V857, I859, L864, A888, C891, V903, W904, Y906, V908, I910, L913, M914,I929, L933, L939, V949, M953, C956, W957, F967, L970, F974, M977, L985714 Sonic hedgehog protein Q15465 A58, A94, M98, C102, L106, L109, A110,V113, L122, V124, W128, L139, H140, A145, V146, I148, M160, L161, A162,A165, V173, I181, C183, V185, A187, A193 715 Transforming growth factor-Q15582 V505, M506, L509, F515, L518, A521, I522, L531, V539, F540, A541,A546, L565, H572, I573, L589, L597, V599, V606, beta-induced proteinig-h3 V608, V624, V625, H626, V627, I628, L632 716 Myosin light chainkinase, Q15746 M1536, I1688, L1714 smooth muscle 717 Neuronalacetylcholine Q15822 A163, H164, A177, I211, L213, V286, I314, V349receptor subunit alpha-2 718 Serine/threonine-protein Q15831 V77, L80,M127, V128, M139, L140, A153, F157, I161, L164, L167, I172, V173, H174,I177, L182, L190, I192, C210, kinase STK11 (EC 2.7.11.1) V236, W239,A241, V243, L245, F255, I267, L285, L286, M289, I303 719Syntaxin-binding protein 2 Q15833 L6, V10, I14, V18, I19, V22, V30, L31,I32, M33, I40, L41, I50, I57, I61, A73, I74, Y75, L77, V84, L87, F91,Y99, A102, I104, F105, F106, L114, L118, L123, L135, A136, F137, V144,F145, L147, A149, L169, L172, A173, I176, A177, L179, C180, A188, I189,L201, A202, V205, L209, L230, L231, I232, M233, A236, A237, V240, L243,L247, F249, M252, A253, L291, V299, V303, L326, H346, H348, L349, A350,C353, V361, L364, C365, L371, L388, I389, V392, L393, L394, I404, V406,L407, L408, L409, Y410, I411, L412, L422, L425, I426, A429, L437, I438,L441, L444, V448, M466, I479, V482, M483, A486, L534, I535, V536, Y537,V538, M539, V542, M544, M547, A549, A550, V553, V563, L564, I565, H569,L571, F576, L577, L580, L583 720 Adiponectin Q15848 A6, L13, P25, V27,L29, G34, G38, I74, P76, I97, A114, F115, V117, F132, F150, L157, Y158,F160, A161, Y162, V166, V171, V173, L175, L183, V201, L202, L203, L205,V211, L213, F234, F237, L238 721 NT-3 growth factor receptor Q16288 I71,L134, L157, L182, A298, V301 (EC 2.7.10.1) 722 Solute carrier family 15Q16348 I653, V660 member 2 723 Acid-sensing ion channel 2 Q16515 F99,L117, Y190, L217, I219, L221, I248, I257, I402, L428, I432 724Interleukin-17A Q16552 C94, C99, V121 725 Calcium/calmodulin- Q16566C63, L74, V117, L126, F127, Y136, A141, A142, A144, V145, L149, A151,L165, L170, L181, I183, A209, V222, W225, dependent protein kinase V227,I229, I233, L234, C236, F241, I254, W266, L271, A273, L276, V277, L280,A294, W299, L317, F320 type IV 726 Laminin subunit alpha-3 Q16787 L272727 Receptor-type tyrosine- Q16827 L920, F923, M930, F938, F942, L945,A957, Y974, V979, Y992, A995, I998, Y1007, I1008, A1009, F1021, W1022,protein phosphatase O M1024, V1025, I1032, I1033, V1034, M1035, L1036,C1047, Y1050, V1065, F1081, I1083, V1092, H1094, Y1097, W1100, I1114,F1117, V1118, V1121, M1132, I1133, I1134, H1135, C1136, V1140, F1146,I1147, A1148, L1149, L1152, V1162, I1164, L1165, V1168, M1171, M1178,V1179, Y1185, F1187, I1188, C1191, V1192 728 Toxin B (EC 2.4.1.—)/strainQ189K3 L562, I578, Y580, I581, V582, A594, F598, A599, V606, L607, F608,A618, L648, F650, F663, L671, I675, I686, I693, 630 (Clostridiumdifficile) L695, M700, F701, Y711, L715, L716, V719, I723, M727, I735,V737, A739, I762, I778 729 Toxin A (EC 2.4.1.—)/strain Q189K5 L9, A13,Y23, I26, L30, L48, L51, I55, F58, L71, L74, I78, V82, L97, H98, F99,V106, Y113, W117, L128, W129, A134, 630 (Clostridium difficile) F135,L136, A152, F170, Y171, M175, I178, I204, I205, L209, I231, I239, L244,Y254, L258, A266, A267, V271, A275, L276, V282, L284, M288, L289, I314,L316, A318, I319, F334, F345, I349, I358, F359, V367, L370, I372, I374,A375, A385, L386, I387, L394, V398, Y406, L409, L413, A416, F430, L434,L446, I449, F457, A461, L467, A472, Y473, A476, Y477, F480, L483, L497,A526 730 Protein Dok-7 Q18PE1 V7 731 Spike glycoprotein Q1HLC5 Y60, M70,L78, F83, F91, F96, A97, V99, F114, A116, I117, I119, F123, V130, V131,L147, I149, V151, C152, M156, C157, H161, I163, L200, H203, F204, F211,A213, F224, Y238, V239, L240, L242, C244, Y252, Y262, L264, C278, A520732 Lipoprotein, Lp Q1HP67 W1640, C1665, C1676 733 Endogenous retrovirusgroup Q1PHM6 A54, F92, M94, M99, M103, I107, V119, V126, M145, L156,A220, I221, C235, V266, I281, L284, V288, I321, C326, I328, K member 113Env L337, V340, V341, I353, Y378, C379, F385, C417, I422, I423, V429,A432, M433, L452, L453, I469, F470, W481, L485, polyprotein V491, I493,V507, I550, V551, L557, L558, A560, I561, A563, M567, L568, V572, I575,L578, V582, I637, I644 734 CTLA-4 protein Q28090 A52, V67, V71, C101,V110, C127, V129, I147 735 Hemagglutinin [Cleaved Q289M7 V7, I20, C21,I22, A26, V33, V36, V43, L49, L50, L58, C59, L61, L67, L69, C72, V74,A75, W77, I78, L79, C84, L87, into: Hemagglutinin HA1 W93, Y95, I96,V97, Y108, L118, L122, V125, F128, F134, A150, C152, H154, L164, L165,L167, L173, L177, V189, chain; Hemagglutinin HA2 L190, V191, L192, W193,V195, H196, H197, Y208, Y214, V215, V217, V218, I243, Y245, Y246, L249,L250, I256, chain]/strain A/New F258, A260, L264, I265, A266, Y269,A270, F271, A272, L273, F277, I281, I282, C291, C295, A301, I302, H312,Zealand: South M330, V331, A348, Y365, A387, I388, L461, L469, H485,C487, C491 Canterbury/35/2000 H1N1 736 HLA class II Q29974 F36, L37,F46, F47, V53, F55, L56, Y59, V67, F69, Y76, W90, L97, A103, C108, V120,V128, L138, L143, L144, V145, histocompatibility antigen, C146, V148,F151, W160, M171, L190, V199, Y200, C202, V204 DRB1-16 beta chain 737MHC class I polypeptide- Q29980 L28, L32, V34, F45, L51, F56, L57, Y59,A66, A73, L96, L100, L113, C119, F133, F140, L141, L145, A158, A162,V165, related sequence B L191, Y194, V223, C225, A227, F230, W239, V268,I272, C282 738 MHC class I polypeptide- Q29983 L28, V34, V49, L51, F56,C59, C64, A73, L96, L100, L113, C119, F133, F140, L141, A162, V165,L191, I221, V223, related sequence A C225, A227, F230, W239, V268, I272,C282 739 Kinesin-like protein KIF7 Q2M1P5 V18, A19, L20, V47, L49, V70,Y71, V75, A88, V90, F91, A92, M104, I119, V120, A123, V143, Y145, L146,V148, F153, L156, V192, V220, F221, V223, L225, F248, F250, V251, A281,L282, V285, I286, A288, I306, I309, L310, L314, A318, M322, I323, A324,C325, V326, L340, A343 740 Endogenous retrovirus group Q2N0S5 A54, A69,M94, M99, V100, M103, L121, L124, L128, L145, C148, M152, F167, L192,A203, C217, A218, A223, I224, K member 24 Env L225, C238, V241, L258,V269, F287, V291, I293, F314, A316, I324, C329, V331, L340, V343, V344,L347, I357, polyprotein F381, C383, F389, L413, C415, I420, I421, I427,A430, M431, Y432, A433, I446, L449, I450, L451, F465, W476, L480, V486,I488, V502, I545, V546, L552, L553, A555, I556, A558, L562, L563, V567,I570, L573, V577, I632, I639 741 Endogenous retrovirus group Q2N0S6 W44,F52, C53, A54, W68, A69, F92, M94, W95, M99, V100, M103, L110, C118,V119, L121, L124, C125, L128, C130, K member 8 Env L145, C148, F150,M152, Y164, F167, L192, C195, I200, A203, C204, C217, A218, A223, I224,L225, C227, C238, V241, polyprotein I250, L258, V269, V285, F287, V291,I293, C295, F314, A316, I324, C329, V331, W336, L340, V343, V344, L347,I357, F359, H372, C376, F381, Y382, C383, L388, F389, L413, C415, I417,I420, I421, I427, A430, M431, Y432, A433, C442, I446, L449, L451, F465,W476, L480, Y483, V486, I488, A494, V502, I545, V546, L552, L553, A555,I556, A558, L562, L563, V567, I570, L573, V577, I632, I639 742 HLA classII Q30154 F36, L37, F46, F47, V53, F55, L56, L67, F69, Y76, W90, L97,A103, C108, V120, V128, L138, L143, L144, V145, C146, histocompatibilityantigen, V148, F151, W160, V171, L190, V199, Y200, C202, V204 DR beta 5chain 743 Hereditary hemochromatosis Q30201 L30, Y32, A49, V53, F58,V59, Y61, L87, L91, I105, L118, L122, C124, H145, L146, A162, A176,L183, C187, L191, protein L223, C225, A227, Y230, W239, I268, V272,C282, V284 744 Genome polyprotein Q32ZE1 I291, C293, V311, V313, V314,L315, C320, V321, V323, M324, A325, V331, I333, L335, V340, Y349, C350,Y351, [Cleaved into: Protein A370, V381, C395, L403, V404, C406, A407,F409, M415, I420, L425, Y427, I429, M430, L431, V433, V455, A464,C/strain Mr 766 (ZIKV) L466, L472, L474, C476, L482, Y488, Y489, L490,M492, H496, W497, V499, F504, H512, L528, V529, V541, L555, H574, L575,C577, L579, M581, L584, C594, F598, V612, V614, V616, Y618, C625, I627,M631, A632, L644, I645, I651, M660, L662, L664, I673, V674, I675, I811,V978, I1008, V1536, M1539, H1545, M1547, V1570, L1574, V1575, Y1577,W1581, V1593, L1595, A1597, V1598, I1613, A1623, V1624, I1637, I1645,L1647, Y1648, V1653, V1660, L1703, I1706, V1707, A1710, V1718, I1719,L1720, A1721, V1726, A1727, M1730, L1734, V1756, L1758, M1759, H1761,F1764, Y1777, L1779, I1781, M1782, A1785, I1793, A1794, A1795, I1799,A1808, A1809, A1810, I1811, F1812, M1813, V1850, V1858, W1859, F1860,V1861, I1870, A1871, C1873, L1874, A1877, I1882, L1884, F1889, W1901,F1903, V1904, I1905, A1914, V1921, I1922, V1938, V1946, A1949, A1951,A1952, I1958, Y1969, M1970, A1976, A1983, A1988, L1991, L1992, I1995,L1997, A2003, L2005, F2030, V2031, L2033, L2039, W2042, L2043, A2044,V2047, A2048, W2059, C2060, I2069, V2078, L2088, A2095, F2107, F2110,A2111, W2528, Y2543, I2548, V2551, A2556, A2559, L2560, A2570, V2571,A2576, I2578, L2581, L2587, V2593, V2594, L2596, C2598, A2607, A2608,V2613, V2616, Y2619, V2648, C2656, L2659, L2660, C2661, V2672, L2678,V2680, L2681, V2684, W2687, L2688, F2695, C2696, I2697, V2699, L2700,C2701, Y2703, M2707, M2711, L2714, L2722, V2725, H2733, M2735, Y2736,W2737, V2738, I2745, V2749, L2755, L2756, I2794, I2801, V2842, L2845,W2849, V2880, V2890, M2891, L2898, I2929, A2939, A2942, F2948, C2964,C2967, V2968, Y2969, M2994, L2996, A2998, L3001, A3005, F3008, L3009,W3014, M3015, V3024, L3032, Y3034, L3036, M3039, A3042, M3047, I3059,A3082, V3085, Y3090, V3094, V3095, V3097, V3107, I3110, I3111, V3123,A3126, L3127, F3130, L3133, V3134, V3135, L3137, I3138, M3141, M3149,L3152, V3161, L3165, L3173, M3176, A3177, V3178, V3184, V3185, F3192,A3195, L3196, F3198, L3199, M3202, V3224, F3226, F3231, I3242, V3243,V3244, C3246, I3253, A3256, A3262, A3270, A3273, A3277, W3280, L3282,F3285, H3286, L3290, M3293, A3294, A3296, I3297, A3300, V3301, V3303,H3316, L3328, W3331, V3334, W3335, H3341, I3354, L3357, A3378, I3381,V3385, I3391, M3399, L3402 745 N-acetylglucosamine-1- Q3T906 L139, L154,F161, V191, A228, L230, L243, L251, A267, L269, L271, A300phosphotransferase subunits alpha/beta (EC 2.7.8.17) 746 Integrinbeta-2-like protein Q3UV74 V127, L129, Y130, F131, L132, M133, V146,L149, L153, L154, L157, I166, F168, I171, F176, F189, L193, L209, A211,V212, V213, V215, A216, I222, L231, V232, L233, Y265, L279, I291, F292,V293, V294, Y302, I309, V324, I328 747 Tyrosine-protein kinase (ECQ3ZC95 F10, L11, F30, L31, L32, L37, I61, C63, V64, V67, F98, F102,V104, Y112, V113, F114, W124, L128, A384, V427, I429, 2.7.10.2) I432,F442, A446, M450, L457, V463, C464, I470, I473, L482, L486, L498, L499,C502, V505, C506, A508, M509, L512, H519, L522, A523, A524, C527, V529,V535, V537, Y545, V561, V568, I580, W581, F583, V585, L586, M587, I590,Y591, I610, L616, A622, V626, I629, M630, C633, W634, F644, L647, I651,V654 748 Envelope glycoprotein Q3ZLH8 A54, H65, A69, V94, V100, M103,V119, I150, L189, C214, A220, I221, C224, C235, V238, I247, L255, I266,I280, gp160 I281, V282, L284, V288, I290, A293, I321, C326, V328, W333,L337, V340, A341, I342, L344, I352, I353, F354, H367, C371, F376, C378,L383, F384, L407, C409, I411, I414, I415, V421, A424, M425, I440, L444,L445, F462, W473, L477, V483, I485, V499, I542, V543, L549, L550, A552,I553, A555, L559, L560, V564, I567, L570, V574, I629, I636 749 CytotoxinL Q46342 L9, V13, Y24, I27, L31, Y46, L49, I52, Y59, L72, F75, L79, V83,L98, H99, F100, Y114, W118, V129, A135, L137, I138, L141, I145, A149,F171, M176, I179, F186, I206, L210, L254, L259, V260, A267, A268, I274,L277, V283, Y284, L285, I289, L290, L317, A319, I320, F335, F346, I359,F360, L363, V368, L371, V373, I375, A376, A386, L387, I388, C395, V399,I403, Y407, L410, F431, I450, L454, F458, L468, V473, Y474, A477, Y478,L481, F501, A527 750 Envelope glycoprotein Q49DS8 I13, V15, L17, V21,I23, I53, C58, I60, L69, V72, A74, L76, I84, V85, H99, F108, C110, L115,F116, I127, L129, C131, I136, I137, V143, A146, M147, I162, L165, L166,L167, F181, W192, L196, V202, I204 751 Cell adhesion molecule- Q4KMG0V737, V739, W741, F754, V756, V782, Y791, F793, V795, A797, V815, I832,I843, L845, F862, I864, I891, Y900, I902, related/down-regulated byM904, C906 oncogenes 752 Cordon-bleu protein-like 1 Q53SF7 V187, I189,L207, L210, I214, C215, L227, L228, L251, A253 753 Receptorprotein-tyrosine Q59FL8 I611, V613, I615, A634, M637, V640, V645, C646,I651, L659, I660, L669, V673, L685, L686, W688, C689, I692, A693, kinase(EC 2.7.10.1) L699, V705, H706, L709, A710, A711, V714, V716, V722,I724, F727, A753, V768, Y771, V773, V775, L778, I794, L798, L804, V814,M818, C821, W822, F832, L835, F839, M842, L850 754 Integrin beta Q59H50C81, C88, C91, C107, L113 755 Filaggrin-2 Q5D862 L33 756 Guaninenucleotide-binding Q5JWF2 L686, L687, L688, L689, I699, M703, I738,L742, A745, I746, I749, L756, I774, F789, A793, L796, V802, C805, C817,protein G A818, F821, I825, I828, F862, M864, V867, A886, I887, F889,V890, V891, Y896, F916, L925, V930, I931, L932, L934, L939, L940, V944,A980, I984, F988, A994, I1015, C1022, I1026, H1030 757 MAGUK p55subfamily Q5T2T1 A73, L96, L108, V164, A173, L185, V188, I201, I212,F214 member 7 758 Dyslexia-associated protein Q5VV43 L354, A356, W372,L393, L395, Y403, F405, V407, V409, V422, V424, A629, L644, W660, A679,V681, L684, F691, KIAA0319 L693, V695, V709 759 Disabled homolog 2-Q5VWQ8 L653 interacting protein 760 Renalase (EC 1.6.3.5) Q5VYX0 L5, I6,A9, L15, C16, A17, A31, V32, W33, A56, L58, L80, V106, A107, I111, I114,I115, I135, W142, V144, F154, I157, V158, L159, V163, I166, I173, L185,Y194, A195, L198, F199, I221, V224, V243, V262, V266, F311, L312, A313,C314, F319, I328, A331, V334 761 Hemagglutinin [Cleaved Q67333 I7, I18,C19, I20, Y22, A24, V31, I34, V41, I47, L48, L56, C57, L59, L65, L67,C70, I72, A73, W75, L76, L77, C82, L85, into: Hemagglutinin HA1 W91,Y93, I94, M95, Y106, L116, L119, L120, V123, F126, L132, A148, C149,V151, M161, V162, W163, L164, A174, chain; Hemagglutinin HA2 M186, L187,I188, I189, W190, V192, H193, H194, Y205, Y211, V212, V214, L219, L236,M240, F242, L246, L247, chain]/strain I253, F255, L261, I262, A263,Y266, F268, I270, I278, M279, C288, C292, A298, I299, H306, H309, I313,V320, L325, A/Singapore/1/1957 H2N2 L327, A328, L331, A345, M357, Y362,A384, F385, A436, L448, H451, V455, L458, V462, L466, C477, H482, C484,C488, M489 762 Envelope glycoprotein Q69994 A52, H63, A67, M92, M97,V98, M101, W109, V117, V124, I172, Y239, C240, A246, I247, C250, C261,V264, I273, gp160 L281, L282, V292, I306, I307, I308, L310, V314, I316,C318, I346, C351, I353, W358, L362, I365, V366, A367, L369, I378, V379,F380, H393, F395, F402, C404, L409, F410, L430, C432, I434, I437, I438,V444, A447, M448, I463, L466, L467, L468, I483, F484, W495, L499, V505,I507, V521, I565, V566, L572, L573, A575, I576, A578, L582, L583, V587,I590, L593, V597, I652, I659 763 Hemagglutinin/A/Viet Q6DQ33 F8, I19,C20, I21, A25, V32, I35, V42, I48, L49, L57, C58, L60, L66, L68, C71,V73, A74, W76, L77, L78, C83, F86, W92, Nam/1203/2004(H5N1) Y94, I95,V96, A99, C106, Y107, L117, L120, L121, I124, F127, I133, A150, C151,Y153, V163, V164, W165, L166, I167, I176, L188, L189, V190, L191, W192,I194, H195, H196, A201, Y207, Y213, I214, V216, L221, M242, F244, F245,I248, L249, I255, F257, F263, I264, A265, Y268, A269, Y270, I272, I280,M281, C290, C294, A300, I301, H308, H311, I315, V322, L327, L329, A330,A351, M363, Y368, A390, I391, A442, L454, V461, L464, V468, L472, C483,H488, C490, C494, M495, A512 764 Tau-tubulin kinase 2 (EC Q6IQ55 V17,V23, Y36, A38, V47, L49, V51, V67, L68, L71, C78, V92, V93, L101, L119,L121, I125, L126, I129, I132, H139, 2.7.11.1) F147, C159, M161, L209,L212, F213, Y214, M215, L216, F219, W226, V235, F255, F258, I262, L276,V279, F280, I284 765 Growth/differentiation factor Q6KF10 F363, C387,A401, I430, C452, C454 6 766 Iodotyrosine deiodinase 1 Q6PHW0 I116,A123, I149, I181, A188, I190, L191, I192, L193, I194, F195 767 Spikeglycoprotein/HCoV- Q6Q1S2 I485, F487, A489, A491, L509, W541, C577,F579, L581, A583, L596, V598 NL63 768 Nucleoprotein/strain Q6TXC0 V33,I36, F39, M43, L56, I57, I63, M66, V67, L68, A70, I96, I116, I119, W120,M136, M137, W139, A153, L154, M163, A/Equine/Santiago/1/1985H3N8 M189,V190, L193, I194, I197, I201, Y219, C223, L226, F230, A234, M238, M239,V242, L256, L259, A263, I265, L266, C275, L276, A278, Y281, F291, Y296,L307, I312, L315, L328, V329, W330, M331, A332, C333, H334, A336, A337,L341, I347, V352, V363, M371, L381, A387, A427, A428, I444, Y487 769Hemagglutinin/ Q6VMK1 V58, I66, C67, L76, C79, L81, L82, I85, C91, A99,L101, I102, I103, C112, L123, L127, I133, I145, C154, Y162, M165,A/Netherlands/219/2003 L168, Y184, A192, L193, I194, I195, W196, I198,H199, Y211, I218, V220, I246, F248, L253, V259, F261, F263, A266, (H7N7)F267, I268, A269, P270, A273, F275, L276, I283, C293, C297, Y298, A353,Y370, A392, L466, L474, H490, C492, C496, A514 770 Neuraminidase (ECQ6XV28 L87, V94, A105, I106, I114, V116, Y121, L122, C124, M131, F132,A133, L134, A145, L158, I159, W161, C176, I177, 3.2.1.18)/strain C184,M191, I193, C194, M195, A202, A204, V205, V206, Y208, A220, L224, C231,V232, C233, V240, V241, M242, A/Budgerigar/Hokkaido/1/1977 I255, I256,Y257, F258, I276, C279, C281, Y282, V285, I288, C290, I291, C292, A299,V303, I304, I306, Y317, L318, H4N6 C319, V322, L323, V350, F353, A354,F355, W362, L363, Y375, M377, L378, V380, A383, I397, I398, A409, F410,I411, F420, F424, Y425, V426, L428, V438, I445, V446, A447, L448, A464,I466 771 Tubulin alpha-1A chain Q71U36 C4, I5, I7, H8, V9, V14, I16,C20, W21, L23, Y24, C25, H28, I30, F52, F53, V62, A65, V66, F67, V68,L70, V74, I75, V78, L86, I93, A99, A100, Y103, A104, I115, V118, L119,I122, L125, F135, L136, V137, F138, H139, L153, M154, L157, L167, F169,Y172, A174, Y185, I188, L189, L195, C200, A201, F202, M203, V204, A208,I209, I212, C213, L227, L230, I231, I234, V235, I238, A240, L242, V250,L252, F255, L259, V260, I265, H266, F267, L269, A270, A273, V288, I291,C295, M302, V303, C305, Y312, M313, C315, C316, L317, L318, Y319, V323,V328, A331, I335, V344, I355, V363, A369, A374, V375, C376, M377, L378,A383, I384, A387, W388, L391, F395, Y399, Y408, F418, A421, M425, L428,Y432 772 Endogenous retrovirus group Q75760 A54, A69, M94, M99, V100,M103, I107, V119, L121, V126, I151, C154, A171, L190, A221, I222, C225,C236, L256, K member 9 Env L257, V267, I281, I282, V283, L285, V289,I291, C293, F312, I322, A325, C327, I329, W334, L338, I341, V342, I343,polyprotein L345, I354, V355, F356, H369, F371, C373, F378, C380, L385,F386, L407, C409, I411, I414, I415, V421, A424, M425, I440, L443, L444,L445, I458, F459, W470, L474, Y477, V480, I482, V496, I539, V540, L546,L547, A549, I550, A552, M556, L557, V561, I564, L567, V571, I626, I633773 Rho-related GTP-binding Q7L0Q8 V50, C52, V53, L54, V55, V60, L65,V66, Y74, A82, V90, V92, V97, L99, L101, A105, Y118, I123, F124, L125,L126, protein RhoU C127, F128, V130, F136, V139, W143, V144, I147, C151,I156, I157, L158, V159, L175, V183, A188, L190, C191, A192, I195, C203,L211, V214, F215, A217, A218, I219 774 Ribonucleoside-diphosphate Q7LG56L34, I52, A66, W78, F88, I89, I92, L93, A94, F95, F96, F111, V115, V117,A120, F123, Y124, H134, M137, L141, I142, reductase subunit M2 B (ECY145, I146, A158, I159, Y164, A169, W171, V187, V188, A189, A191, A192,V196, F197, F198, A203, A204, I205, 1.17.4.1) L208, L213, M214, L217,I224, F234, A235, C236, M238, F239, V251, I254, I255, A258, V259, F265,L266, A269, L270, V272, L274, I275, M282, I286, A290, L294, F303 775Ankyrin repeat and sterile Q7Z6G8 V815, W818, L819, L831, F836, M842,M847, L852, I857, I866, A869, I870, V889, L893, F905, I933, I939, A1064,alpha motif domain- F1065, A1084, C1085, I1105, L1107, V1109, V1114,I1130, I1133, F1146, A1147, Y1148, I1149, C1160, V1162, containingprotein 1B F1163, A1171, I1174, L1178, A1181 776 E3 ubiquitin-proteinligase Q7Z6Z7 A1335, A1338, A1348, L1352, F4001, V4019, V4021, V4026,F4027, L4034, M4042, W4065, Y4066, I4069, M4073, HUWE1 (EC 6.3.2.—)L4080, I4093, F4107, F4109, V4110, I4113, V4114, A4115, A4117, L4124,C4126, F4128, F4132, Y4133, I4136, M4146, F4174, V4207, V4210, C4211,M4215, F4226, F4230, I4234, L4238, I4239, I4241, L4247, I4251, I4278,F4281, A4284, L4285, A4294, V4300, F4311, F4323, I4325, C4341, L4345,L4347, Y4350, L4356, L4360, A4363, I4364 777 Hemagglutinin [CleavedQ82559 A26, L28, C29, L30, A34, V41, V51, L57, V58, I66, C67, V73, C79,L81, I82, M85, L86, C91, F94, L101, F102, I103, F109, into:Hemagglutinin HA1 C112, Y113, Y115, Y120, A121, L123, V127, A128, L133,F140, A153, C154, F162, F163, L166, L169, L179, Y193, chain;Hemagglutinin HA2 W195, I197, H198, H199, Y210, V217, V219, I245, I247,Y248, I251, V252, I257, L258, I260, L266, V267, A268, F273,chain]/strain I289, C296, I297, I303, I324, L331, A332, A349, W358,Y366, A388, A440, L462, L470, C481, F482, I484, H486, C488,A/Equine/Kentucky/1/1981 C492, I493, I496, A510 778 Fusion glycoproteinF0 Q84850 I233, F237, V247, M251, L257, I261, M274, V281, F342, V349,C382, A412, V414, C416, C422, A424, V450 779 Regulating synaptic Q86UR5V600, L602, A614, L616, L618, A633, I635, A644, L650, V656, W659, L664,V672, I676, V685, I687, V689, L746, membrane exocytosis V748, L750,L759, V761, V763, A766, V782, M784, V818, F823, L828, I830, V832, L846,I849, L853 protein 1 780 Fermitin family homolog 3 Q86UX7 L73, L74,I358, V378, F380, L404, I422, V426, L437, C439, A446, W448, M449, A450,C452, L454, A455 781 Transmembrane protease Q8IU80 I504 serine 6 (EC3.4.21.—) 782 Sodium channel subunit Q8IWT1 L51, C53, L64, W68, L79,I80, V84, I101, I114, I116, L118, L121, C131, V133, L149 beta-4 783Interferon lambda-3 Q8IZI9 L27, L45, A59, L65, L75, L82, L85, A93, L94,A96, L98, L102, L126, C136, A161, C169, V174, L181 784 Interferonlambda-2 Q8IZJ0 L31, L49, A63, L69, L89, A100, L106, C140 785 Ablinteractor 1 Q8IZP0 V451, A453, L465, I473, V475, I476, C488, F495 786Kin of IRRE-like protein 3 Q8IZU9 I438, C440, I442, A452, W453, L483,I485, I488, Y497, C499, A501, L514 787 Envelope glycoprotein Q8J581 C50,A51, H62, A66, M91, M96, V97, M100, I104, L107, V116, L143, I210, Y212,C213, A219, I220, C223, C234, V237, gp160 I246, L254, I265, I267, I279,I280, V281, L283, V287, I289, C291, I320, A323, C325, V327, W332, L336,V339, A340, L343, I351, I352, H366, F375, C377, F383, L408, C410, I412,I415, I416, A422, A425, M426, I441, L444, L445, L446, F460, W471, L475,Y478, V481, I483, V497, I540, V541, L547, L548, A550, I551, A553, L557,L558, V562, I565, L568, V572, I627, I634 788 Endogenous retrovirus groupQ8JDI3 A54, H65, A69, F92, M94, M99, V100, M103, I107, L110, V126, I145,M152, V173, I175, L189, F206, I211, Y213, C214, K member 21 Env A220,I221, C235, V238, I247, L255, V266, I280, I281, V282, L284, V288, I290,I321, C326, V328, L337, V340, V341, polyprotein L344, I352, F354, H367,F369, C371, F376, C378, F384, L405, C407, I409, I412, I413, V419, A422,M423, I438, L441, I442, L443, F457, M464, W468, L472, Y475, V478, I480,V494, I537, V538, L544, L545, A547, I548, A550, L554, L555, V559, I562,L565, V569, I624, I631 789 Neuroligin-4, X-linked Q8N0W4 I55, V70, Y73,V76, Y78, F88, V109, C110, L132, C146, L147, L149, I151, V153, V168,M169, V170, I172, H173, L190, A191, V196, I197, V198, I199, I201, Y203,I207, F210, L211, A218, L224, I228, A230, L231, W233, I234, V238, V248,I250, F251, A257, C259, V260, L262, L263, A276, I277, I278, A288, I299,L300, A301, V304, C306, V315, L318, L326, I338, I349, Y365, I367, M368,L369, V380, V390, V399, F402, V403, L416, I420, L440, L443, V450, A457,H460, Y470, A471, F472, A488, V493, Y495, V496, F497, F508, L519, V523,M524, Y526, W527, F530, A531, A558, L570, I572, A584, F589, I603 790Jouberin Q8N157 V1057, A1058, I1072, I1078, V1080, F1101 791Gamma-aminobutyric acid Q8N1C3 I436 receptor subunit gamma-1 792TGF-beta-activated kinase 1 Q8N5C8 L13, L16, V27, V28, M32, C42 andMAP3K7-binding protein 3 793 Inactive dipeptidyl peptidase Q8N608 L69,V94, V95, L117, V139, A142, A155, V158, L180, A183, L192, I193, Y194,I195, I200, L230, Y231, L235, A241, 10 L251, A252, L254, I256, I266,Y280, L294, Y295, V296, V297, L299, L306, Y320, I321, V324, V333, V334,W336, L337, I345, C349, F385, V388, H400, V401, A402, V425, I438, F440,L452, C475, F489, L490, C493, L503, L545, L547, L549, A562, L563, L564,L565, V576, L588, V594, I595, V596, A597, L609, I615, V622, V631, I647,Y655, A657, F668, C670, A675, L680, A684, A686, F687, L692, V711, I721,H723, V730, F732, H734, L742, I773, F777, L781 794 Proprotein convertaseQ8NBP7 V80, L82, A95, L98, A102, F122, V124, L130, A134, V140, I143,F150, I161, V180, V182, Y183, L184, L185, H193, I196, subtilisin/kexintype 9 (EC H229, L230, A231, V233, V234, A242, A245, M247, L250, V252,I271, L283, V284, V285, L286, L287, C301, L304, 3.4.21.—) V309, V310,L311, V312, A314, A315, A322, A328, A330, V333, I334, V336, A338, V346,V359, L361, F362, A363, I368, A371, A388, A389, A390, H391, V392, A393,I395, A396, A397, M399, L400, A409, L411, L415, I424, F429, V441, A442,A473, A475, L484, C486, F489, C509, A511, V520, A522, I523, A524, C526,C527, A542, C588, A594, I596, H597, A598, C600, C601, A603, L606, V622,A625, L632, C654, V656, V672, A674, A676, C678, C679 795 Cytoplasmicdynein 2 heavy Q8NCM8 L1352, F1356, F1368, C1411, L1419, L1438, M1476,V1484, V1496, L1511, L1515, W1626, C1640, M1644, Y1655, chain 1 C1671,L1675, A1678, V1699, A1736, V1750, L1751, A1753, V1754, A1764, F1788,V1815, A1826, V1872, A1901, L1943, A1962, V1975, V1976, I1977, V1978,W1989, L1992, A1995, M2008, I2053, V2069, F2094, A2105, I2113, C2182,L2200, F2208, F2254, F2275, W2278, L2279, L2301, A2304, L2354, V2355,L2374, A2376, V2395, V2403, L2427, V2474, V2476, V2480, L2524, I2526,A2531, F2548, F2572, L2634, I2640, F2646, L2651, L2653, A2654, V2668,A2701, V2708, L2712, F2722, L2751, H2777, L2780, C2803, V2805, M2808,I2819, C2862, Y2872, F2875, A3208, A3209, A3317, V3318, L3324, V3332,V3353, I3360, A3383, V3390, L3403, A3496, L3509, A3522, F3571, A3572,F3575, W3648, Y3651, C3657, A3694, L3724, L3740, A3754, M3755, A3771,W3776, L3777, A3811, L3822, A3861, A3868, F3870, H3871, A3872, C3874,Y3927, I3931, L3944, L4021, L4040, V4090, Y4140, L4141, L4144, I4151,A4202, I4217, C4225, C4248, A4301 796 Semaphorin-6D Q8NFY4 L150, A179,Y199, I211, Y252, A256, V269, F292, L297, A407, V417, L465, C521 797Protein CASC5 Q8NG31 F2149, Y2151, I2154, L2156, I2158, L2197, I2202,V2233, C2236, L2239, I2243, L2265, L2267, F2269, F2278, I2280, L2282,I2309, Y2322, V2326, V2327, I2330 798 Envelope glycoprotein Q8Q7Z9 M23,I24, I30, L69, A100, I101, C115, V118, V131, L135, L136, V146, I160,I161, V162, L164, V168, I170, C172, A192, F193, I196, M202, H206 799CTLA4 Q8TDA6 A54, C58, Y60, V69, V71, V73, C85, L95, V112, I116, C129,V131, I149 800 2-amino-3- Q8TDX5 I5, H6, H8, I9, L10, L17, A37, L39,C53, M63, A72, L73, M79, F80, Y82, L92, C93, L96, L100, F111, L114,L117, M119, carboxymuconate-6- A125, M129, C132, V141, I143, V147, L152,L157, V160, Y161, A163, A164, C169, L171, F172, V173, A202, I203,semialdehyde decarboxylase M206, I207, V211, V220, C221, F222, A223,F229, F262, L274, L277, V286, I287, I305, M308, L319, A321, A324, F327(EC 4.1.1.45) 801 Partitioning defective 3 Q8TEW8 I12, L434, I499, L509,I527, I533, L550, V553, L558, A566, I584 homolog B 802 Protein Shroom3Q8TF72 A30, L32, A63, L70, V76, I79, A91, L102, L104, V106 803Intelectin-1 Q8WWA0 C41, C48, L58, C70, L81, V82, A83, V85, C94, W100,A129, Y139, L147, I149, H151, V152, W161, L167, L176, L183, I186, Y187,W200, V236, F238, V240, F241, A246, A247, A249, L250, C251, M254, H264,C265, F272, C280, F283, F286, I303, A306, A307, L309, L310, F311, Y312804 Palladin Q8WX93 F1020, C1022, V1024, I1032, W1034, C1058, L1060,Y1073, I1075, A1077, L1090, C1152, M1154, C1156, V1158, L1193, I1195,V1198, Y1206, C1208, A1210, L1253, C1255, W1267, I1291, L1293, I1295,A1298, Y1306, V1308, A1310 805 Relaxin receptor 2 Q8WXD0 C52, L59 806Nesprin-2 Q8WXH0 A191, V203, W210, A215, F216, A218, I219, I220, L242,A245, F246, A249, V264, I274, M275, Y277, V278, A279, F281, L282 807Mucin-16 Q8WXI7 L14325, F14327, I14329, L14332, I14353, L14357, L14360,V14389, C14393, A14399, I14407, F14411, L14421, V14431 808 Hemagglutinin[Cleaved Q91MA7 A27, L29, C30, L31, A35, V42, V52, L58, V59, I67, C68,I74, C80, L82, I83, A85, L86, L87, C92, F95, L102, F103, V104, into:Hemagglutinin HA1 F110, C113, Y114, Y116, Y121, A122, L124, V128, A129,L134, F141, A154, C155, F163, F164, L167, L170, Y177, L180, chain;Hemagglutinin HA2 L193, Y194, I195, W196, V198, H199, H200, Y211, V218,V220, I246, I248, Y249, I252, V253, V258, L259, I261, chain]/strainA/Hong L267, I268, A269, F274, I290, C297, I298, I304, V325, L332, A333,A350, W359, Y367, A389, A441, L463, L471, Kong/1/1968 H3N2 C482, F483,I485, H487, C489, C493, I494, I497, A511 809 Alpha-N-acetylneuraminideQ92185 W68, F78, C85, C86, F92, M105, Y107, I117, C138, A139, V140,V141, I146, L147, C152, I156, F161, V162, C165,alpha-2,8-sialyltransferase L167, V178, L184, V185, I191, I192, L199,F206, Y213, A222, F223, L233, V235, Y236, L239, A244, F262, W263, (EC2.4.99.8) A270, L273, A282, A283, L284, L286, C287, V290, Y293, W296,F298, I307, Y311, Y312, L316, F321, A323, M324, L334, L340, C347 810Nicastrin Q92542 C50, L53, L54, C62, I73, V85, M95, V96, L98, F103,M108, L111, L121, A122, V123, W164, L171, F176, F178, I180, F181, L182,L183, V191, I192, L212, C213, A214, M215, L217, C230, C248, L251, V256,W257, M259, V275, V276, V277, A278, A279, L282, F288, A292, A295, A298,V299, A300, F302, V303, L306, A307, A308, A309, A311, L312, A315, V325,M326, F327, V328, F329, F330, F335, Y337, I338, M347, V354, F362, L365,V368, L376, M378, V394, L397, L401, F430, V439, L441, A442, L471, A484,L487, A488, V490, A491, V493, L494, L498, Y499, L501, A502, V511, A513,V518, L521, L522, F525, A529, F534, L538, H553, I555, V566, V567, A570,L571, V605, C620, A628, A630, A634, A658, I660 811 Protein NDRG1 Q92597Y73, C92, A119, I145, W183, H214, L284 812 Nectin-2 Q92692 L52, C54,V68, W70, A83, F85, L103, L127, Y138, F142, L156, V180, A181, C183,V236, C238, V240, L255, V257, V263, W272, L314, C329, V331 813 Ryanodinereceptor 2 Q92736 L14, V20, V21, L22, C24, A26, L35, C36, L37, A38, A39,I64, C65, F67, L69, L78, L113, Y115, A118, I119, L121, H123, L130, C131,A144, V147, L149, C158, W160, I162, V175, L181, L183, L192, V203, A205,A206, W212, V214, L228, L234, L236, H238, C244, L245, V247, V260, Y262,V267, A271, L274, W275, L277, I289, F295, L297, H299, V300, Y305, L306,L315, L316, A322, F329, F331, I354, C361, I363, L372, A391, I403, L405,A416, V418, I419, F426, F429, L447, V452, L456, L459, I460, F463, L482,L488, F489, M494, V498, C501, I502, L505, F514, A518, I529, L530, L533,L536, A539, L540, W697, A698, V718, C757, I766, V791, V792, A886, F921,V996, A1000, H1004, L1050, V1054, V1115, W1117, L1128, A1134, A1136,F1137, V1162, C1164, V1166, M1173, F1175, F1195, V1204, V1443, W1445,I1446, L1459, V1465, V1467, L1469, I1507, L1518, F1520, A1542, F2720,A2725, H2727, H2729, L2779, M2782, M2828, M2840, M2844, A2845, A2889,I2892, L2893, L2896 814 Serine protease HTRA1 (EC Q92743 C53, C76, L132,L150, V175, I179, A182, V183, V184, H185, I186, L188, F207, I208, I215,V216, A219, V221, V222, 3.4.21.—) V228, V230, A240, A249, I251, A252,I254, I256, V279, V280, A281, I282, V297, I317, A321, I323, L332, V333,V339, I340, I342, F353, A354, I355, I360, F363, I383, A395, L398, A412,I414, A423, L428, V433, I434, I437, V448, I452, L458, M460, V462, I471,V473 815 Secreted frizzled-related Q92765 A63 protein 3 816Ras-responsive element- Q92766 C701, C792, C805, C1514 binding protein 1817 Disks large homolog 3 Q92796 I132, L134, L141, A146, V154, I160,I162, A170, A171, V179, V183, L184, V186, V191, A199, A202, L203, A206,V210, L212, V214, V227, L229, L236, I240, I255, I257, A265, A266, L278,V281, L286, A294, L298, V305, L307, V309, A310, I387, L389, I409, F410,V411, A420, L426, I432, V435, A448, A451, V459, I461, A463 818 X-linkedretinitis Q92834 A13, V14, H46, A48, V49, V50, L56, M58, F59, L67, V81,V89, A92, H98, L100, V101, V108, A110, L119, I133, A153, pigmentosaGTPase A154, L155, L161, M163, W164, I172, H201, A203, F204, V205, L211,V213, F214, L222, L228, H254, V256, V257, regulator V263, F266, L274,L280, I289, H306, A308, L309, L315, M316, F319, C343, H360, M361, V362,V363, A365 819 Ectodysplasin-A Q92838 L90, V251, L253, V262, L271, L293,V295, Y301, I303, V307, V309, Y311, I312, F314, A318, Y320, V322, I336,C346, (Ectodermal dysplasia I360, V362, I369, I371, M373, F380, A382protein) 820 Canalicular multispecific Q92887 A668, V669, L680, A683,M684, I1330, V1332, V1333, L1343, L1347, F1348 organic anion transporter1 821 Tumor necrosis factor Q92956 C53, C54, C57 receptor superfamilymember 14 822 Lipoma-preferred partner Q93052 C444, L451, C476, I483,A494, F500, C524 823 Homogentisate 1,2- Q93099 L61, Y62, W97, F112,V113, L119, C120, L131, A132, I133, I135, F136, L137, C138, C146, F147,F154, L155, I156, dioxygenase (EC 1.13.11.5) V157, L163, I165, F169,M172, V174, I179, C180, V181, I182, M186, F188, I190, Y199, I200, L201,V203, F208, L221, F227, V239, V245, I246, L253, A256, F263, V265, A267,W268, Y277, V300, L301, A303, A313, F315, I317, F342, L345, A397, F398,F400, Y423 824 Interleukin-22 receptor Q969J5 F41, L45, F61, V62, C118,L120, Y131, V135, F152, V176, L178, L183, V205, A241, I243 subunitalpha-2 825 SH3 domain-containing Q96B97 A4, V6, L18, I20, I26, W37,F48, V53, C103, V105, L117, L119, I125, V127, L140, F147, I152, C272,V274, L286, I288, kinase-binding protein 1 V294, W307, F318, V323 826Interleukin-17 receptor A Q96F46 L48, V93, A94, I96, W98, A112, L114,F129, L135, F144, F149, V150, V151, Y157, V159, V161, H163, V182, M190,C196, L217, V219, F221, Y230, I232, L234, V281, I283, F287 827Leucine-rich repeat and Q96FE5 V55, C57, L76, L78, I83, L86, F91, L97,L100, L102, V107, A114, F115, L118, L121, L124, L131, V138, L142, L145,immunoglobulin-like L148, I150, L158, F163, L166, L169, L172, V174,L179, A186, F187, L190, L193, L196, L198, C201, A210, L211, L214,domain-containing nogo L217, L220, L222, I230, L241, L244, I246, W249,L252, C259, L260, L265, L268, I270, A282, L286, L289, I299, L310,receptor-interacting protein L313, L318, L323, A330, F331, L334, L340,V342, L347, L350, V354, L361, L364, L366, L371, L377, V380, F381, 1L387, F389, C396, V402, F407, A424, F444, C446, W458, L482, V484, A487,Y495, C497, A499, A510, L512 828 PDZ and LIM domain Q96HC4 L8, W14, L28,I30, A39, V49, V50, I53, A58, M61, A66, I70, L77, M79, L81, C420, I427,L432, C446, M453, F458, protein 5 V459, C467 829 E3 ubiquitin-proteinligase Q96J02 L20, I22, V24, V43, V45, V47, V71, V73, L79, F81, V83,L95, I102, L106, L113, L122, L135, I137, L139, L328, L440, Itchy homologF456, F496, F535, C539, I550, V552, F558, I565, L573, V579, I580, V592,W596, F597, L600, L611, F638, F640, I641, F644, I645, A646, M647, A648,Y664, I667, L677, F705, A742, F757, F761, I764, L765, L770, F773, L778,L782, W793, I809, F812, F815, V816, M825, L827, L828, V831, F842, F854,C855, I856, C871, L875, L877, L886, L890, A893, I894 830Serine/threonine-protein Q96J92 L210 kinase WNK4 (EC 2.7.11.1) 831Roundabout homolog 3 Q96MS0 C143, I572, L574, I591, V616, F627, V629,A631 832 NACHT, LRR and PYD Q96P20 L10, L14, F25, L29, L54, A55, M58,A67, W68, A69, M70, A71, I74, F75, A87 domains-containing protein 3 833Interleukin-17F Q96PD4 C102, C107, V129 834 SLIT and NTRK-like proteinQ96PX8 Y61, L63, L65, L70, L73, F78, L87, M89, L94, A101, F102, L105,V108, L111, I113, I118, F121, L129, L132, L135, 1 A137, L142, A149,F150, L153, L156, L159, L161, I166, V173, F174, L182, L184, L189, V197,L198, I201, I207, L208, L209, W214, C216, L220, L223, A234, V239, C241,L247, L252, I387, I390, F395, L401, L404, L406, I411, F419, L422, L425,L428, M430, L435, L438, F443, L446, L449, L452, V454, I459, I462, F467,M470, L473, L476, L478, L483, V490, F491, L496, L499, L501, F506, V514,L515, I524, L526, W531, I537, F540, L556, F569 835 Membrane-associatedQ96QZ7 F318, Y377, L475, L496, I498, A507, M513, V518, I519, V520, V522,V527, L528, V535, V548, L550, L552, C553, guanylate kinase, WW and I646,I686, V689, V694, V702, V715, L717, V719, I842, L844, I865, I867, A876,L888, I889, V891, V896, V904, A911, PDZ domain-containing V917, L919,V921, V999, I1001, I1038, A1047, L1053, V1062, I1075, V1086, L1088,V1153, L1166, L1176, A1187, protein 1 M1193, I1199, I1202, A1215, L1218,V1226, L1228, L1230 836 Envelope glycoprotein Q993A8 A13, M38, V44, M47,I51, V63, V70, I97, L136, A167, I168, C182, V185, I194, L202, L203,V213, I227, I228, V229, gp160 L231, V235, I237, C239, M269, C274, I276,W281, L285, I288, A289, L292, I302, I303, F304, H317, F319, C321, F326,C328, L333, F334, L359, C361, I366, I367, V373, A376, M377, I392, L395,L396, L397, I410, F411, M418, W422, L426, V432, I434, V448, I491, V492,L498, L499, A501, I502, A504, L508, L509, V513, I516, L519, I523, I578,I585 837 Neurogenic locus notch Q99466 C472, C510, C548, C586, C965,L1638, H1639, A1641, A1642, A1650, L1671, H1672, A1674, V1675, A1679,V1682, homolog protein 4 C1683, L1686, L1705, M1706, L1707, A1708,A1709, L1716, L1720, A1737, L1738, H1739, A1741, A1742, A1749, A1750,L1753, L1771, F1772, L1773, A1774, A1775, V1782, A1783, L1786, V1806,A1807, L1815 838 Protein deglycase DJ-1 Q99497 A6, L7, V8, I9, L10, A11,A14, V25, M26, V33, A36, L58, A61, Y67, V69, V70, V71, L72, A79, L82,V88, L92, I102, A103, A104, I105, A111, L112, L113, H115, I117, V123,M133, M134, I152, L153, F164, A165, I168, V169 839 Histone H2B type 1-NQ99877 V42, V45, L46, A59, M63, V67, I70, F71, I74, A75, A78, A82, I90,I95, A98, V99, L103, A108, A111, A118 840 Myocilin (Myocilin 55 kDaQ99972 V269, W270, W286, I288, V298, Y301, F307, H316, L318, A327, V329,L334, F336, V344, I345, Y347, L349, I360, subunit) (Trabecular A363,L381, V383, L388, V390, I391, I401, L403, L406, L411, V426, A429, F430,I431, I432, L436, V449, M476, meshwork-induced L486, W489, M494glucocorticoid response protein) [Cleaved into: Myocilin, N-terminalfragment (Myocilin 20 kDa N-terminal fragment); Myocilin, C-terminalfragment (Myocilin 35 kDa N-terminal fragment)] 841 Semaphorin-3C Q99985L305, L449, L472, I473, I491, L526 842 Sclerostin Q9BQB4 C80, L146, C165843 Programmed cell death Q9BUL8 L22, A41, A46, A51, L81, F100, L103,A107, L110, L114, I117, F127, I134, L141, V145, V148, L160, F167, F174,protein 10 V190, F191, A194, L197, I198, I204, L205, F208 844 Brother ofCDO Q9BWV1 V622, V624, W626, F639, V641, I668, Y677, F679, V681, A683,V701, I718, I729, L731, F748, I750, I777, Y786, I788, M790, C792 845Complement C1q tumor Q9BXJ0 A108, L123, F125, F143, C145, Y151, F153,V155, V159, L164, L168, L199, V205, V207, F227 necrosis factor-relatedprotein 5 846 Periaxin Q9BXM0 V44, A53 847 Complement factor H- Q9BXR6Y53, I70, C87, V110, I127, C129 related protein 5 848 Disintegrin andQ9BZ11 L212, L214, Y215, I216, V217, A218, L237, V240, V244, L247, L248,I253, W263, L279, F282, L283, A298, L300, metalloproteinase domain-L301, V328, A339, A340, M343, A344, I347, L351, M373, L405, C433, C444,C457, C462, C488, C495 containing protein 33 849 NACHT, LRR and PYDQ9C000 L13, L21, F24, L28, V53, A54, L57, A66, A70, W74, L82, V136,F365, F801, A824, V825, L828, L842, L844, C847, L849, domains-containingprotein C854, L870, L872, L877, A882, C886, L899, C904, C910, C911,L918, L927, L929, V939, L942, C943, L946, L953, 1 L956, L958, M967,L971, L974, I983, L1379, V1382, L1389, I1390, V1393, V1396, V1399,L1400, L1403, L1408, V1416, M1426, L1429, L1444, A1447, L1448, L1459 850MCG4778 Q9D1H1 L75, F77, I79, L82, I88, I103, L107, L110, V140, C144,A150, I158, F162, L172, V182 851 Amyloid beta A4 precursor Q9DBR4 V594,L611, A614, V630, M632, V639, V641, C654, V656, L659, F661, M662, V664,F671, A672, F673, I674, C684, protein-binding family B V686, F687, C689,A693, V696, V700, A703, N738 member 2 852 Sperm-egg fusion proteinQ9EQF4 M28, C47, W50, C55, C86, A93, C95, F96, C99, L103, V120, V123,L125, C126, C130, W133, C137, F169, F173, L179, Juno C180, I183, F188,C200, L201, V216 853 Fibroblast growth factor 23 Q9GZV9 H41, L42, L53,I55, A72, L73, I85, L94, C95, M96, C113, F115, V126, L135, V136, F157854 ADP-ribosylation factor-like Q9H0F7 V20, L21, C22, L23, I33, I34,F58, M70, A89, I90, F92, V93, I94, V104, L109, L112, I118, I125, L126,F127, F128, protein 6 A129, V143, L149, C160 855 Magnesium transporterQ9H0U3 L44, I54, M56, L64, V65, Y72, V74, I75, V76, M77, F78, C90, A93,F97, L100, A101, I114, F116, V119, V127, F128, protein 1 F139, A163,I166, I170 856 ATP-binding cassette sub- Q9H221 L195, L234, L264, A422,A546, A548, A549 family G member 8 857 ATP-binding cassette sub- Q9H222V72, I81, M82, C83, I84, L85, L95, L96, L139, L142, V144, L148, Y150,A155, V168, M172, I185, A204, M214, L215, family G member 5 F216, L235,A239, I244, V245, I249, I263, A264, F273, M280, F284, F298, Y301, Y329,L371, V375, A415, L423, F426, V427, M435, A438, F442, V448, Y458, M463,M464, A466, Y467, V471, A478, F482, C486, Y487, L490, L492, A505, L506,A508, H510, L511, L518, L521, V530, V534, C571, I574, L575, V576, F580,C613, A616, L627, F642 858 Cadherin-23 Q9H251 I42, L55, F78, V87, L89,V103, F105, V107, V118, I120, V122, V154, V187, V189, V205, A207, L222,I224 859 DnaJ homolog subfamily C Q9H3Z4 L16, Y17, L20, I31, A53, I60,A63, L67, I75, V95 member 5 860 SPARC-related modular Q9H4F8 I416calcium-binding protein 1 861 Anthrax toxin receptor 1 Q9H6X2 L45, Y46,F47, I48, L49, V55, I62, Y63, F65, V66, L69, L78, M80, F82, I83, V84,F85, L109, L113, M120, F124, A127, I131, I145, I146, A147, L148, F159,A165, V175, C177, V178, V180, L188, I191, A192, L208 862 Pleckstrinhomology Q9HB21 L14, F30, L32, F39, F81, V82, M83, L92, W103, V106,L107, C198, L215, I220, I235, C246, L257, F258, I260, V269,domain-containing family A V284 member 1 863 Transient receptorpotential Q9HBA0 L487 cation channel subfamily V member 4 864Interleukin-21 Q9HBE4 L35, V39, L42, A56, C64, A68, F69, C71, F72, L77,I89, L96, F129, L130, F133, L136, L137, I141 865 E3 ubiquitin-proteinligase Q9HCE7 I15, L17, V19, A22, L25, L33, A38, I40, V42, L68, I76,I78, V80, I86, F94, I133, V135, F324 SMURF1 866 Roundabout homolog 2Q9HCK4 C110, A435, L437, W451, L473, L478, Y486, C488, A490, A501, L503,V538, L540, I557, V582, F593, V595, A597, V637, V652, V654, I665, Y668,V670, L699, I710, V712 867 Golgi-associated PDZ and Q9HD26 L291, I313,I315, A324, L330, A335, I336, A338, V339, L344, A352, L356, I363, F365,V367 coiled-coil motif-containing protein 868 Neurexin-3-beta Q9HDB5I96, L113, V115, F117, I125, L126, V127, I129, L139, L141, I143, I148,V150, F152, I159, I161, V168, V176, A185, L187, V189, V194, L204, F207,I213, I215, F224, L228, L231, Y233, V238, L239, V255, V261 869Neuraminidase (EC Q9IGQ6 L85, I106, V114, V116, F121, I122, F132, F133,L134, L158, C161, A178, W179, A181, A183, C184, L191, I193, I195,3.2.1.18)/strain A/Brevig A202, V203, A204, L206, L224, A232, C233,V234, F239, I241, M242, A251, Y253, I255, I258, V263, H275, Y276, C279,Mission/1/1918 H1N1 C281, Y282, V288, C290, V291, C292, V304, F306,L310, C318, V321, F322, F349, F351, Y353, V357, W358, I359, (Influenza Avirus (strain F371, M373, I374, F387, I393, V394, F406, V407, M418,C421, F422, W423, V424, L426, W437, I443, F445 A/South Carolina/1/1918H1N1)) 870 Spike glycoprotein Q9J3E7 L79, V87, F92, F100, I104, A106,V108, F123, I126, V127, I128, F132, V139, V140, I141, I148, V152, C153,C158, C165, A201, F202, F206, F213, A215, F226, I232, V241, L242, F244,C246, Y258, V260, A482, Y891, V900, V906, A994, A1053, L1067, I1113 871Interleukin-23 subunit alpha Q9NPF7 C33, L40, A44, L82, C89, L90, I93,H94, L97, Y100, F109, L124, L128, L131, L150, L169, V173, A176, V179,F180 872 SLAM family member 7 Q9NQ25 F39, I51, W53, L90, L95, L122,V124, Y125, L128, W164, L180, C195 873 Serine protease inhibitor Q9NQ38C30, F33, C44, C63, C66, C161, L173, C194, C197, C225, L237, C258, C261,C297, L309, C330, C333, C367, L379, Kazal-type 5 C400, C403, C437, L449,C470, C473, C496, L508, C529, C532, C567, L579, C600, M602, C603, C632,L644, V653, C665, M667, C668, C707, L719, C740, C743, C774, L786, C807,C810, C849, L861, C882, C885, C916, L928, C949, C952, C1014, Y1021,L1027, C1028, I1040 874 Ubiquitin carboxyl-terminal Q9NQC7 V131, V133,V146, V165, L167, C193, V195, F196, V236, L238, V249, L255, V265, V267,C286, I295, A476, I488, hydrolase CYLD (EC A502, L504, A531, I594, L603,L607, F608, C609, L610, F611, A612, Y633, L640, V645, V654, I659, L662,L666, F685, 3.4.19.12) L689, I693, L700, I717, I730, F745, L752, I754,M756, L775, I777, L780, C788, C802, F816, A863, V864, L865, C866, A874,F875, V876, L886, F888, V906, C909, V912, A935, C945, Y947 875 Potassiumvoltage-gated Q9NS40 I30, A32, C44, F48, C49, M51, V59, C64, C66, I82,A83, V96, Y98, I112, I127, A766, A781, L785, I790, I807, F808, channelsubfamily H V825, A827, L833, V844 member 7 876 Septin-11 Q9NVA2 F42,I44, L45, C46, V47, L57, M58, V92, L94, L96, V99, Y114, I117, I121,F125, L129, A149, C150, L151, I154, M169, L172, V176, I178, I179, I181,I182, A183, F196, I200, M228, F234, V237, A252, V262, F270, L273, M276,L285, H293, Y294 877 Alpha-parvin Q9NVD7 L268, V272, H275, L276, V283,L286, F290, L296, V297, L299, M300, V308, V327, A330, M334, L339, I349,L358, V360, L361, L364 878 Sodium channel subunit Q9NY72 L43, C45, V60,W62, V103, I105, V107, Y118, C120, V122 beta-3 879 Endoplasmic reticulumQ9NZ08 F47, Y57, Y63, L65, I67, L71, F76, V82, I84, A86, I93, I94, L95,A105, L107, L115, L123, I131, A132, L133, L139, L140, aminopeptidase 1(EC V141, Y145, V147, V148, I149, Y151, Y163, L177, A178, F182, A186,A187, A190, F191, C193, F194, A201, F203, I205, 3.4.11.—) I207, F236,M242, Y245, L246, V247, A248, F249, I250, I251, V267, V269, A271, A279,Y281, A282, L283, A285, A286, L289, L290, Y293, F297, L308, A309, A310,I311, F314, A318, M319, W322, L324, Y327, A331, L332, L333, I347, V351,A352, L355, A356, H357, W359, F360, L363, M366, W369, L372, W373, L374,F378, A379, F381, M382, V387, L394, V396, F405, A407, M408, A412, V419,V423, M432, V436, A442, C443, I444, L445, L448, F457, I461, L465, L478,W479, M482, V517, M520, M521, W524, F530, L532, I533, I535, V542, M544,Y549, W563, V565, L567, L582, F600, M604, Y607, Y608, I609, V610, L620,L624, V631, A637, L639, I640, A643, L646, I654, A657, L658, L660, Y663,L664, V673, L680, M687, V695, F699, F702, L703, L731, L732, A735, C743,A747, V767, A770, V771, A776, W782, L785, I801, A804, L805, C806, L814,L817, L818, I827, F832, I835, L836, I839, A849, W850, L853, L860, F864,I871, M874, V875, F882, V891, F895, L898, L905, I915, I929, L933 880Interleukin-1 receptor Q9NZN1 L66, V347 accessory protein-like 1 881Programmed cell death 1 Q9NZQ7 V21, M36, I38, C40, L53, V55, W57, M59,I64, I65, F67, Y81, L92, A97, A98, L99, I101, V104, Y112, C114, I116,I126, ligand 1 V128, A132, Y134, L153, C155, A157, A163, W167, V193,L197, F207, C209, F211, L214, L224, I226 882 Potassium voltage-gatedQ9NZV8 L66, F84 channel subfamily D member 2 883 Signal-regulatoryprotein Q9P1W8 A49, L51, C53, V64, W66, I104, I109, C119, V120, F166,C168, F173, W182, A211, V213, L215, V224, C226, V228, gamma L244, A247,I248, V269, C271, V273, F276, L283, W285, C329, V331 884 Spastin (EC3.6.4.3) Q9UBP0 V116, A123, A130, A145 885 Glyoxylate Q9UBQ7 V9, V11,L23, A24, A26, V49, A50, A52, L55, L56, C57, V63, L68, V77, I78, I93,A112, A115, L118, L119, C123, V156, reductase/hydroxypyruvate I158,A167, I168, A169, L172, L181, A192, L205, A206, F211, I212, V213, V214,C226, F230, F231, A238, V239, reductase (EC 1.1.1.79) F240, I241, V248,L254, A257, A264, A266, L268, V270, L282, A309, A310, L313 886 Beta-1,4-Q9UBV7 L95, A96, V97, L98, V99, F111, V112, M115, L119, I128, V130,L131, A142, L144, I145, V147, I159, A160, H162, galactosyltransferase 7L166, L167, L173, Y175, H184, V185, A186, L190, V200, I203, L204, L205,L206, Y211, M217, F231, I235, L242, L258, A262, A305, L310, I312, C324887 Fibulin-5 Q9UBX5 C166, C286 888 5′-AMP-activated protein Q9UGJ0M265, C270, I273, V289, A292, L296, A304, L306, L318, I320, F323, I324,I326, L327, L341, I346, A368, L370, A373, kinase subunit gamma-2 V374,L377, L385, V387, L399, H401, I404, L405, L408, F420, L425, I430, I445,A448, L449, I457, L460, V462, Y473, V478, A482, L490, V494, L498, C511,L517, I520, V529, L532, V533, V534, V535, I545, L547, I550, L551, A553,L554 889 Deleted in malignant brain Q9UGM3 A1896, V1899, I1901, V1910,C1911, A1920, V1922, V1923, C1924, A1981, V1983 tumors 1 protein 890Interleukin-20 receptor Q9UHF4 M50, L54, L82, C95, L97, A110, V112,I151, V153, M172, L179, Y181, V183, V185, V216, V218 subunit alpha 891Doublecortin domain- Q9UHG0 I141, L143, I144, I158, V169, V173, L187,V195, Y207, V208, A209, V210, Y220 containing protein 2 892 DNApolymerase subunit Q9UHN1 L69, C73, F78, L79, L106, L110, W114, V118,V125, A130, L185, A189, L190, Y193, L197, Y206, L208, A209, C214,gamma-2, mitochondrial A237, L239, V240, W241, F242, W255, W262, W263,F266, F273, L289, F293, W295, I303, L303, L311, L322, V335, (EC 2.7.7.7)L336, V338, L342, M346, L347, A348, Y349, V371, L372, L374, L378, A379,V383, A384, L385, V387, L395, C399, L402, L406, L407, L418, I437, L438,V441, V443, I453, L471 893 C-type lectin domain family Q9UHP7 C86, F87,C103, A108, L110, A111, V113, L122, H131, W132, I133, L135, F155, C163,A164, L166, I183, C184 2 member D 894 Apolipoprotein Q9UIR5 W35, C60,C71 895 Gap junction delta-2 protein Q9UKL4 C62 896 Endoplasmicreticulum Q9UKM7 V253, F257, A260, Y264, A268, L274, L287, L289, L291,I292, A294, L295, M298, A310, V314, L318, F320, V326,mannosyl-oligosaccharide L328, I335, L336, L339, L340, A342, F351, A355,F358, L362, A365, I372, V377, I379, V395, I401, L403, F405, L408,1,2-alpha-mannosidase (EC F417, V421, V424, I428, L438, V439, I443,L458, A462, Y466, Y468, L470, I474, Y487, A490, I491, V494, L498, F509,3.2.1.113) V510, L513, M522, C527, L529, L533, A534, H545, L548, A549,L552, M553, C556, M559, L567, V572, V585, L596, V601, L604, F605, L607,Y616, I623, L624, I641, V644, M656, F660, L661, L665, Y667, L668, L670,L671, V685, F686, A690, H691, L693 897 Disintegrin and Q9UKQ2 C423,C434, C452, C453, C485 metalloproteinase domain- containing protein 28898 Frizzled-4 Q9ULV1 I50, C53, A75, L79, L94, F97, L98, C99, V101,Y102, V103, C117, C121, V124, C128, L132, F135, L143 899 Heat shockfactor protein 4 Q9ULV5 L21, L24, L27, V28, I37, F46, V48, F54, V58,L59, F71, L75, F101, F106, L114, V117 900 Neurogenic locus notch Q9UM47C194, C428, C466, C504, C617, C884, C921, C1405, C1417, F1437, C1446,C1451, F1456, C1475, A1476, L1513, homolog protein 3 V1514, L1515,V1517, L1524, F1531, L1535, L1539, V1582, L1584, I1586, A1604, A1607,A1608, L1611, A1613 901 Unconventional myosin-VI Q9UM54 A9, I31, A43,C63, L65, A71, L73, L74, I77, I86, V90, I93, L94, I95, A96, I103, I112,V127, F128, A129, I130, A131, A134, M138, V140, I147, I148, V149, A155,V164, Y167, L168, A185, L188, L189, A191, F192, A195, F206, F209, I212,F214, V220, I235, Y245, H246, I247, F248, Y249, L251, C252, L265, F271,Y273, L274, Y281, F282, I318, M320, M324, I327, L337, V340, V341, A342,V344, L345, L347, I350, L372, C375, A376, L378, L379, L381, L386, L390,A416, A419, A422, L423, A424, V427, Y428, L431, F432, V435, V436, V439,I452, V454, L455, F471, Y475, C476, L480, F483, F484, I488, L489, Y496,C514, I515, L517, I518, I525, I528, L529, F543, V547, F577, I578, I579,V586, Y588, F593, L605, I609, I617, L651, L654, L655, L658, F665, I666,C668, I669, I685, L689, M694, V697, L698, M701, Y705, A709, L714, Y718,Y721, L729, F734, C735, A737, L738, F739, L753, V756, F757, F758, F763,A764, I769, L777, L780, V784, I1171, F1180, A1204, H1205, F1206, A1212,M1215, L1226, V1227, M1235, L1245, F1258, W1262, L1271, A1274, I1275,A1280, A1285, L1289 902 Rho GTPase-activating Q9UNA1 A761, A763, L775,F783, V786, L795, I806 protein 26 903 Tumor necrosis factor ligandQ9UNG2 A82, F84, C100, V101, L109, I111, Y117, I119, V123, A124, V137,L139, Y140, I155, V158, L164, I170, L172, V180, superfamily member 18W187, I189 904 Protein unc-13 homolog A Q9UPW8 L1494, L1500 905Neuraminidase (EC Q9W7Y7 I87, V95, V97, F102, I103, F113, F114, L115,L139, C142, A159, W160, A162, A164, C165, L172, I174, I176, A183,3.2.1.18)/strain A/Hong V184, A185, L187, L205, A213, C214, V215, F220,V222, M223, A232, Y234, I236, I239, V244, H256, Y257, C260,Kong/156/1997 H5N1 C262, Y263, A266, I269, C271, V272, C273, V285, F287,C299, V302, F303, F330, F332, Y334, V338, W339, I340, F352, genotypeGs/Gd M354, I355, F368, I374, I375, F387, I388, M399, C402, F403, W404,V405, L407, W418, I424, F426 906 Hemagglutinin [Cleaved Q9WFX3 V7, I20,C21, I22, A26, V33, V36, V43, L49, L50, L58, C59, L61, L67, L69, C72,I74, A75, W77, L78, L79, C84, L87, into: Hemagglutinin HA1 W93, Y95,I96, V97, C107, Y108, L118, L122, V125, F128, F134, A151, A152, C153,Y155, A158, L165, L166, W167, chain; Hemagglutinin HA2 L168, Y175, L178,V190, L191, V192, L193, W194, V196, H197, H198, Y209, Y215, V216, V218,Y223, A233, M244, chain]/strain A/Brevig Y246, Y247, L250, L251, I257,F259, A261, L265, I266, A267, Y270, A271, F272, A273, L274, I282, I283,C292, Mission/1/1918 H1N1 C296, A302, I303, H313, I317, V324, L329,M331, A332, A349, M361, Y366, A388, I389, A440, L452, V459, L462,(Influenza A virus (strain V466, L470, C481, H486, C488, C492, M493A/South Carolina/1/1918 H1N1)) 907 Genome polyprotein Q9WMX2 L754,V1061, L1070, A1071, C1073, V1074, V1077, C1078, W1079, V1081, A1085,I1097, L1108, V1109, L1120, [Cleaved into: Core protein L1130, L1132,I1140, V1142, V1158, L1161, L1169, C1171, A1176, V1177, I1179, F1180,A1190, A1192, V1193, p21/genotype 1b (isolate F1195, V1196, V1198,M1201, Y1244, V1251, V1253, L1254, A1259, A1260, M1268, I1291, Y1293,Y1296, A1301, I1312, Con1) (HCV) I1314, C1315, C1318, I1326, L1327,I1329, V1332, A1336, A1341, L1343, V1344, V1345, L1346, A1347, I1373,F1375, I1380, I1385, L1391, I1392, F1393, C1394, C1400, L1403, L1407,V1432, V1434, V1435, A1436, L1440, F1444, F1448, V1451, I1452, F1470,A1481, Y1499, L1517, C1518, C1520, Y1521, A1526, Y1528, L1539, Y1542,L1555, W1558, V1561, I1568, F1572, L1586, V1587, A1588, A1591, C1594,W1608, L1611, H1619, L1624, L1625, L1628, I1641, I1645, M2025, C2029,I2035, C2052, F2060, I2062, C2070, Y2090, V2091, V2093, V2102, M2105,F2122, V2128, F2147, L2160, L2440, L2449, L2450, V2456, Y2457, A2458,A2464, Y2483, V2486, M2490, A2492, A2494, V2497, A2499, A2507, C2508,Y2522, A2524, V2527, A2534, I2538, L2545, L2546, I2557, C2565, A2576,L2578, V2580, L2584, V2586, V2588, C2589, A2593, L2594, V2597, V2598,L2601, A2604, V2605, Y2610, V2620, L2623, A2626, M2634, F2636, Y2638,V2647, I2652, I2658, Y2659, C2661, C2662, A2665, A2668, A2671, I2672,L2675, L2679, Y2680, L2685, C2693, C2698, A2700, V2703, L2704, C2708,L2712, C2714, A2718, A2719, A2720, A2721, C2722, A2725, L2727, M2732,L2733, V2734, L2739, V2740, V2741, I2742, C2743, A2753, L2755, F2758,A2761, M2762, Y2765, A2767, I2782, V2789, A2792, Y2801, L2803, L2811,A2812, A2814, A2815, L2828, I2831, I2832, A2835, L2838, W2839, A2840,I2843, L2844, M2845, H2847, F2848, F2849, L2858, A2861, C2864, I2866,A2869, C2870, Y2871, I2873, L2876, L2878, I2881, I2882, L2885, A2890,F2891, V2904, A2905, C2907, L2908, L2911, V2913, V2918, W2919, A2923,V2926, L2930, L2931, A2937, A2938, C2940, L2944, F2945, A2948, A2960,A2961, F2970, A2972, Y2974, I2979 908 Tumor necrosis factor ligandQ9Y275 L112, C146, L147, L149, V166, A177, L178, I185, V187, F193, F194,I195, Y196, V199, Y201, M208, H210, I212, superfamily member 13B L224,L226, M236, C245, A248, L253, L259, L261, A262, I263, A268, V276, F278,F279, A281, L282 909 Cofilin-2 Q9Y281 V11, V14, M18, A35, V36, L37, F38,I47, I48, I55, V57, Y68, F71, V72, L75, C80, Y82, A83, L84, Y85, A87,V100, F101, W104, A109, Y117, I124, F128, V137, L149, L161 910 Ragulatorcomplex protein Q9Y2Q5 L11, L23, L24, L25, A42, A46, V81, A82, I83, L89,L90, L91, C92, M93, L104, A108 LAMTOR2 911 Kinesin-like protein KIF3AQ9Y496 V15, V17, V18, V19, I46, V48, V76, I85, V88, I96, A98, M110,I122, F127, I130, Y149, L150, I152, V157, L160, M195, H216, F224, I226,I235, L246, L248, V249, A252, L267, V283, I284, L302, L310, M318, C319,A320, I322, A325, L336, A339, A342, I345 912 Neurexin-3 Q9Y4C0 F337,L576, L582, L585, F711, I824, F875, F896, L909, L949, L988, Y993, V1022,I1101, L1118, V1120, F1122, I1130, L1131, V1132, I1134, L1144, L1146,I1148, I1153, V1155, F1157, I1164, I1166, V1173, V1181, A1190, L1192,V1194, V1199, L1209, F1212, I1218, I1220, F1229, L1233, L1236, Y1238,V1243, L1244, V1260, V1266 913 Dystrobrevin alpha Q9Y4J8 C258, L266,C270 914 Kallikrein-4 (EC 3.4.21.—) Q9Y5K2 I31, A46, A47, L48, V59, L60,V66, L67, A69, C72, I79, L81, L83, A99, A114, L117, M118, L119, I132,I135, C148, V150, W153, V168, C178, C192, A193, L211, C213, L217, L220,V236, Y237, L240 915 CD2-associated protein Q9Y5K6 Y4, V6, L18, I20,I26, L38, F49, V54, C113, V115, L127, L129, I135, F157, V162, C274,L288, F290, I296, F320, A325 916 Brefeldin A-inhibited Q9Y6D5 F654,A679, Y711, F722, A739, A769, I776, I822 guanine nucleotide-exchangeprotein 2 917 Cadherin-10 Q9Y6N8 L63, F102, I111, A113, I117, L127,A131, V147, I148, I150, V169, V182, I217, I218, V235, I237, A239, V255,I257, A293, F317, L346, V348, A350, V371, I373 918 Tumor necrosis factorQ9Y6Q6 C47, C50, A113, C114, C133 receptor superfamily member 11A

Example 4: Assays Measuring Alterations in Conformational Dynamics

Alterations in conformational dynamics can be measured by standardmethods known in the art. In preferred embodiments, alterations inconformational dynamics can be shown by measuring changes in meltingtemperatures, in urea-induced equilibrium unfolding studies, and/orGibbs free energy as compared to the starting protein.

Changes in melting temperature can be shown by the following protocol.For example, a peptidogenic protein (0.20 mg/ml) and a starting protein(as a control) is heated from 10° C. to 72° C. in a 0.1 cm quartzcuvette with a heating rate of 1 degree×min−1 controlled by a Jascoprogrammable Peltier element. The dichroic activity at 209 nm and thephotomultiplier tube voltage (PMTV) are continuously monitored inparallel every 0.5° C. All the thermal scans are corrected for thesolvent contribution at the different temperatures. Melting temperature(Tm) values are calculated by taking the first derivative of theellipticity at 209 nm with respect to temperature. All denaturationexperiments are performed in triplicate (see Lori et al., PLoS One, 5;8(6):e64824 (2013)).

A change in urea-induced equilibrium unfolding can be shown by thefollowing protocol. A peptidogenic protein (final concentration 40ug/ml) and a starting protein (as a control) is incubated at 10° C. inincreasing concentrations of urea (0-8 M) in 25 mM Tris/HCl, pH 7.5, inthe presence of 0.2 M NaCl and 2 mM DTT (for non-disulfide containingproteins). After 10 min, equilibrium is reached and the intrinsicfluorescence emission, absorbance at 287 nm, and/or far-UV CD spectra(0.5-cm cuvette) are recorded in parallel at 10° C. To test thereversibility of the unfolding, a peptidogenic protein is unfolded at10° C. in 7.0 M urea at 0.4 mg/ml protein concentration in 25 mMTris/HCl, pH 7.5, in the presence of 2 mM DTT and 0.2 M NaCl. After 10mM, refolding is started by 10-fold dilution of the unfolding mixture at10° C. into solutions of the same buffer used for unfolding containingdecreasing urea concentrations. The final protein concentration is 40ug/ml. After an incubation period of 15 min to 24 h, the intrinsicfluorescence emission, absorbance at 287 nm, and/or the CD spectra arerecorded as a function of urea concentration at 10° C. (see Lori et al.,PLoS One, 5; 8(6):e64824 (2013)).

Alterations in Gibbs free energy can be shown by the following protocol.In order to measure Gibbs free energy, differential scanning calorimetry(DSC) experiments are performed on a VP-DSC (Microcal Inc., Northampton,Mass.) instrument at a scan rate of 1.5 deg/minute. Where possible,temperature-induced unfolding of a peptidogenic protein is checked forreversibility by comparing first and second DSC scans. It is understoodthat reversibility of folding and unfolding is not a requirement for thepeptidogenic proteins described herein. The partial molar heat capacityof the protein, Cp,pr(T), is obtained from the experimentally measuredapparent heat capacity difference between the sample (containing proteinsolution) and reference (containing corresponding buffer solution)cells, ΔC_p{circumflex over ( )}app (T). Protein concentration ismeasured spectrophotometrically using a known molar extinctioncoefficient. Analysis of the heat capacity profiles according to atwo-state model is done using non-linear regression routine NLREG andin-house written scripts. The standard thermodynamic functions underreference conditions are calculated as:

Δ H_(ca l)(T) = Δ H(T_(m)) + Δ C_(p)(T − T_(m)) $\begin{matrix}{{\Delta\; S(T)} = {{\Delta\;{S\left( T_{m} \right)}} + {\Delta\; C_{p}{\ln\left( {T/T_{m}} \right)}}}} \\{= {\frac{\Delta\;{{Hcal}({Tm})}}{Tm} + {\Delta\;{Cp}\;{\ln\left( {T/{Tm}} \right)}}}}\end{matrix}$Δ G(T) = (T_(m) − T)(Δ H_(ca l)(T_(m))/T_(m) − Δ C_(p)) − T Δ C_(p)ln (T/T_(m))

Where ΔH(T), ΔS(T), and ΔG(T) are the enthalpy, entropy and Gibbs energyfunctions of a peptidogenic protein, respectively, ΔHcal is the enthalpyof unfolding at the transition temperature Tm, and ΔCp is the heatcapacity of unfolding (see Loladze et al., J. Mol. Biol. 320, 343-357(2002)).

Example 5: Assays Measuring Peptidogenicity

One of the intracellular conditions that may participate in processingof the peptidogenic proteins as described herein is proteolysis. Theinfluence of the differential stability of the peptidogenic proteins onproteolysis can be determined using one of several in vitro or ex vivoassays.

(a) Cathepsin L Proteolysis

In one embodiment, examination of the behavior of the peptidogenicproteins toward proteolysis is measured by subjecting them to the actionof cathepsin L, one of the enzymes known to be critical in proteinantigen processing (Hsieh, C. S., deRoos, P., Honey, K., Beers, C., andRudensky, A. Y. (2002) J. Immunol. 168, 2618-2625). Susceptibility ofthe peptidogenic proteins to proteolysis is assessed using lysosomalcathepsin L. The peptidogenic proteins (0.5 ug/ul) are incubated withvarious amounts (e.g., 1.5 munits) of enzyme in 50 mM sodium acetatebuffer, pH 4.5, for various lengths of time at 37° C. Digestion isstopped using 0.1% TEA, and proteolysis is monitored by reversed-phaseHPLC on C18 reverse phase columns (Vydac, Hesperia, CA). Elution of theproteolytic products is carried out with a linear gradient ofacetonitrile/water containing 0.1% TEA.

(b) Proteolysis Using Alpha-Chymotrypsin and Carboxypeptidase Y

In another embodiment, examination of the behavior of the peptidogenicproteins toward proteolysis is measured by subjecting them to the actionof alpha-chymotrypsin and carboxypeptidase Y. Alpha-chymotrypsin is anendopeptidase which cleaves at the carboxyl terminus of aromatic aminoacids; carboxypeptidase Y is an exopeptidase which removes amino acidssequentially from the carboxyl terminus. Proteolytic digestion withthese enzymes is specific for unstable conformations, hence, theconformational stability of the peptidogenic proteins determines theirresistance/susceptibility to proteolytic digestion. The peptidogenicproteins at 1 mg/ml in 0.5 ml of 20 mM HEPES-buffered saline, pH 7.5,are incubated at 37° C. with 100 ug of alpha-chymotrypsin from bovinepancreas and carboxypeptidase Y from yeast. Each incubation isterminated at various time-points and the digested samples are stored at−20° C. until analyzed. Samples are analyzed by sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS-PAGE), through a 15%acrylamide gel and under reducing conditions, then stained withCoomassie Brilliant Blue for visualization.

(c) Proteolysis Using Lysosomal Extracts

In another embodiment, examination of the behavior of the peptidogenicproteins toward proteolysis is measured by subjecting them to the actionof lysosomal extracts of bone marrow-derived dendritic cells. Thepeptidogenic proteins are incubated at various concentrations in thepresence of equal amounts of proteins from crude lysosomal extracts frombone marrow-derived dendritic cells. The mixtures are incubated in 0.1 Msodium citrate buffer, 0.5% Triton X-100, and 2 mM dithiothreitol at pH4.5. Each incubation is terminated at various time-points and thedigested samples are stored at −20° C. until analyzed. Samples areanalyzed by SDS-PAGE. The experiments are repeated with and withoutprior adsorption of peptidogenic proteins onto an adjuvant such asaluminum hydroxide. Bone marrow-derived dendritic cells are purifiedwith use of anti-CD11c microbeads from bone marrow cultured ingranulocyte macrophage-colony stimulating factor. See, for example,Delamarre et al., FIG. 4.

(d) Proteolysis after Internalization by Bone Marrow-Derived DendriticCells

In another embodiment, examination of the behavior of the peptidogenicproteins toward proteolysis is measured by labeling them with FITC perthe manufacturer's protocol, incubating bone marrow-derived dendriticcells with the FITC-proteins, and measuring the percentage of FITC+,CD11c+ cells over time. Bone marrow-derived dendritic cells are loadedwith 0.5 mg/ml of the FITC-labeled peptidogenic proteins for 1 hour, arewashed, and then are cultured at 37° C. for various amounts of time.FACS is then used to determine the percentage of FITC+, CD11c+ cells ateach time point subtracted to the percentage of FITC+, CD11c+ cells attime 0 h. This represents the percentage of proteolysis of thepeptidogenic proteins. The experiments are repeated with and withoutprior adsorption of FITC-labeled peptidogenic proteins onto an adjuvantsuch as aluminum hydroxide.

Example 6: Antibody Production and Sequencing

Ig-seq of antibody repertoires may follow previously described protocols(10, 29) with minor modifications. B cells can be isolated from theserum, spleen, or other tissues of hyperimmunized rabbits. In order toreduce the complexity of the sequencing library, this population can besorted to enrich for CD19⁺CD3⁻CD27⁺CD38^(int) memory B cells or B cellsthat recognize the target antigen (5, 30, 31). These cells are thenlysed and mRNA is isolated using standard methods, and reversetranscribed to cDNA using 5′ RACE with 3′ primers specific for the IgHor IgL constant region (9, 32). The cDNA library is then amplified withprimers containing the required paired-end adapter sequences andoptional barcodes to enable quantification of template and errorcorrection by averaging multiple reads (8, 9).

Complete determination of antibody sequences requires identifying nativeVH-VL pairs. As each VH and VL sequence is encoded by a separate mRNA,clonal sequencing may be performed by isolating single B cells insubnanoliter volume wells (5) or microemulsion (9) prior to mRNAisolation, reverse transcription, and overlap extension or linkage PCR.As an alternative, endogenous VH-VL pairs can be identified throughpartial cross-linking of purified Fabs prior to LC-MS/MS. Under theappropriate conditions, this will result in a fraction of the Fab heavyand light chains forming interchain crosslinks, and the resultingpeptide masses will be used to determine native pairing.

In order to identify the antibodies raised in response to a mixture ofpeptidogenic proteins, sequence information can be combined with datafrom high-resolution mass spectrometry. Protein A-purified IgGs can bedigested with papain to release the two Fabs from the Fc domain. Thesecan then be immunoaffinity purified on a custom column prepared usingthe peptidogenic protein immobilized on a solid support, the eluted Fabsproteolytically digested, and the peptide products subjected to massspectrometry. The resulting peptide masses can be compared with thecomplete antibody sequencing data to identify the CDR sequences thatrecognize the antigen. Pairing of IgG VH and VL sequences can beaccomplished through chemical cross-linking of the immunoaffinitypurified Fabs prior to the proteolytic digest; Young et al havedemonstrated the feasibility of this approach (33).

Example 7: Immunization Using a Mixture of Peptidogenic Proteins

Methods of raising antibodies in mammals are well known in the art. Inone example, polyclonal antiserum against peptidogenic proteins israised by immunization of pathogen free rabbits with a total of 500 μgof a mixture of peptidogenic proteins over a period of two months. Forexample, the peptidogenic proteins can be dissolved in PBS andemulsified with an equal volume of Freund's adjuvant. After the finalbooster, the serum of the rabbits can be separated to determine thetiter of the polyclonal antiserum. To obtain monoclonal antibodies, 4-6week old Balb/c mice can be immunized with a peptidogenic protein (forexample 4 times with 2 week intervals with 10-100 μg/injection dissolvedin Freunds complete adjuvant for the first injection, and Freund'sincomplete adjuvant for subsequent immunizations). Splenocytes areisolated and fused with a fusion cell line such as Sp2/0 myeloma cells,followed by limiting dilution. Growing clones are screened using forexample an enzyme-linked immunosorbant assay (ELISA). 96 cells platesare coated with peptidogenic proteins or with a control protein. Theculture supernatant is added, followed by washing and addition of alabeled anti-mouse antibody for detection. After limited dilutioncloning of the peptidogenic protein-specific antibody producinghybridomas stable hybridomas are obtained. From each cell, supernatantis collected and by affinity chromatography using protein A sepharosecolumns monoclonal antibodies can be purified.

Example 8: Another Example of Immunization Using a Mixture ofPeptidogenic Proteins

In an additional animal model, groups of 5 mice (C57BL/6J; Jackson Labs)can be subcutaneously immunized with 5 μg of endotoxin-free peptidogenicproteins emulsified in alum, which is the adjuvant most commonly used inhuman vaccines. Three weeks later, mice are bled and the presence ofpeptidogenic protein-specific antibodies can be determined by titeringthe seras by ELISA (direct binding of antibodies in sera to wild typeBPTI or APP-KI coated, directly or indirectly (via a biotinylated tagand streptavidin), on the wells). To confirm that the peptidogenicproteins have a similar conformation as the starting protein,competitive inhibition assays are performed in which titrated amounts ofstarting protein and peptidogenic proteins are pre-incubated with theseras prior to adding to the starting protein coated plates. Thisprovides additional evidence, with an immunological probe, that the 3Dstructure of the peptidogenic proteins has not been compromised by theengineered mutations.

To determine whether the peptidogenic proteins result in bettersecondary antibody responses, groups of mice can be immunized asdescribed above, and 6 weeks after the primary immunization they can beimmunized a second time. One week post-secondary immunization, mice arebled and antigen-specific antibody responses are determined by ELISA asdescribed above. Mouse dendritic cells are pulsed in vitro with thepeptidogenic proteins that can generate a strong antibody response, and24 hrs later the peptidogenic protein-derived peptides presented byMHCII are isolated and their masses analysed by liquid chromatographyand mass spectrometry (LC/MS). These studies require large numbers(>10⁷) of dendritic cells which are purified from mice previouslyinjected with a mouse tumor line expressing FLT-3L, a cytokine thatdrives dendritic cell development in vivo (the spleens of these micefill up with dendritic cells; Segura et al, 2009). To allow for peakidentification and the quantiifcation of MHCII-peptides by massspectrometry, the peptidogenic protein can be biosynthetically labeledwith stable isotopes such as 13C and 15N (during production of therecombinant protein—see above) prior to feeding to the DCs (Hoedt et al2014).

Example 9: Immunization Using Sequences Encoding a Mixture ofPeptidogenic Proteins

Methods of directly injecting polynucleotides into animals are welldescribed in the art. See, for example, U.S. Pat. Nos. 5,676,954;6,875,748; 5,661,133. Briefly, using the known degeneracy of the geneticcode, polynucleotides encoding a mixture of peptidogenic proteinsdescribed herein can be synthesized using standard DNA synthesistechniques. The polynucleotide(s) can then be directly injected into theanimal, such as, for example, mice. Specifically, a mixture ofpolynucleotides encoding the mixture of peptidogenic proteins can beinjected into the quadriceps muscles of restrained awake mice (female6-12 week old BALB/c or Nude, nu/nu, from Harlan Sprague Dawley,Indianapolis, Ind.). In one embodiment, 50 μg of a polynucleotide in 50μl solution using a disposable sterile, plastic insulin syringe and 28G½ needle (Becton-Dickinson, Franklin Lakes, N.J., Cat. No. 329430)fitted with a plastic collar cut from a micropipette tip can be used toinject the mice, as described in Hartikka, J., et al., Hum. Gene Ther.7:1205-1217 (1996)).

Alternatively, 6-week old Sprague Dawley female mice (body weight 20-25grams) can be given 5000 ppm ZnOSO4 in their drinking water beginning 24hours prior to injection. This amount of zinc has been shown to be ableto activate the metallothionein promoter. Each mouse is then injectedintravenously through a tail vein puncture with a 25 gauge needle with30 μg of polynucleotides encoding the mixture of peptidogenic proteinscomplexed with 150 μg liposome (Lipofection TM) in a total volume of 30μl. In one embodiment, the polynucleotides mixture injected into themice encodes for different peptidogenic proteins relating to the samestarting protein. Alternatively, a library of peptidogenic proteins canbe encoded by the mixture of polynucleotides, wherein the libraryrelates to different starting proteins. Animal care should be maintainedthroughout the study and should be performed in compliance with the“Guide for the Use and Care of Laboratory Animals”, Institute ofLaboratory Animal Resources, Commission on Life Sciences, NationalResearch Council, National Academy Press.

After the injected polynucleotide encoding the peptidogenic proteins aredelivered into the cells in the animal, the peptidogenic proteins arethen expressed in vivo. The peptidogenic proteins can then stimulate theproduction of antibodies specific to the peptidogenic proteins. Theseantibodies can be isolated and used as a polyclonal mixture or furtherisolated into single species or monoclonals. The process of the immuneresponse and production of antibodies against foreign antigens in vivoare well known in the art. Unlike the traditional protocols of antibodygeneration, the platform invention described herein allows thesimultaneously raising of a group of antibodies against multiplepeptidogenic proteins (whether or not they rely on the same startingprotein). This simultaneous production of antibodies to multipleproteins using a mixture of polynucleotides has the potential to changehow antibody production is currently being performed.

Example 10: Immunization Using mRNA Encoding Peptidogenic Proteins

The methods of directly injecting in vitro transcribed (IVT) mRNA intoanimals are also well known in the art. See, Sahin et al., Nat Rev DrugDiscov. 2014 October; 13(10):759-80; Kariko et al., Mol Ther, 2008November; 16(11):1833-40; Kariko et al., Nucleic Acid Res, 2011,November; 39(21):e142; U.S. Pat. No. 6,511,832. For example, linearizedDNA plasmid templates which encode a mixture of peptidogenic proteinscan be used. All mRNAs can be designed to contain 5′ and 3′ untranslatedregions, the open reading frames, and long poly(A) tails, which can helpdetermine the translational activity and stability of the mRNA moleculeafter its transfer into cells.

For example, mRNAs (including a poly(A) tail) encoding peptidogenicproteins can be synthesized using triphosphate-derivatives ofpseudouridine and 5-methylcytidine (m5C) (TriLink) to generate amodified nucleoside containing RNA. A 5′-cap can be added to the mRNAsby supplementing the transcription reactions with 6 mmol/l3′-O-Me-m7GpppG, a nonreversible cap analog (New England Biolabs,Beverly, Mass.) and lowering the concentration of guanosine triphosphate(3.75 mmol/1). Purification of the transcripts can be performed by TurboDNase (Ambion, Austin, Tex.) digestion followed by LiCl precipitationand 75% ethanol wash. The concentrations of RNA reconstituted in watercan be determined by measuring the optical density at 260 nm. Efficientincorporation of modified nucleotides to the transcripts can bedetermined by HPLC analyses. All RNA samples can be analyzed bydenaturing agarose gel electrophoresis for quality assurance. Lipofectin(Invitrogen, Carlsbad, Calif.) and mRNA are then complexed in phosphatebuffer in order to enhance transfection. To assemble a 50 μl complex ofRNA-lipofectin, first 0.4 μl potassium phosphate buffer (0.4 mol/1, pH6.2) containing 10 μg/bovine serum albumin (Sigma, St. Louis, Mo.) isadded to 6.7 μl DMEM, then 0.8 μl lipofectin is mixed in and the sampleis incubated for 10 minutes. In a separate tube, 0.25-3 μg of RNA isadded to DMEM to a final volume of 3.3 μl. Diluted RNA is added to thelipofectin mix and incubated for 10 minutes. Finally, the RNA-lipofectincomplex is further diluted by adding 38.8 μl DMEM.

The RNA encoding the peptidogenic proteins can then be injected into themouse models described herein. In general, a composition comprising 60μl final volume with 1 μl lipofectin and different amounts ofpolynucleotides encoding the peptidogenic proteins are injected into thelateral vein using a 1-ml syringe with a 27G½ needle (Becton Dickinson,San Diego, Calif.). Alternatively, the polynucleotides can be injectedvia intramuscular, intradermal, intranasal, subcutaneous, intravenous,intratracheal, and intrathecal deliveries. After the polynucleotides aredelivered into the cells, the peptidogenic proteins are synthesized invivo. The immune responses triggered by the peptidogenic proteins andthe subsequent production of antibodies in the animals are describedherein.

Example 11: Affinity Maturing Antibodies to Peptidogenic Protein UsingPhage Display

Once antibodies have been raised to the peptidogenic proteins bypresenting and allowing the peptidogenic protein to undergo processingby an antigen presenting cell such as described in the Examples herein,the resulting antibodies can be matured using a display approach. Forexample, a library of phage displaying scFvs or Fabs derived from B cellmRNA encoding the target-specific antibodies can be screened in an assayto identify those phage displaying scFvs or Fabs that immunospecificallybind to a peptidogenic protein or to a starting protein. Phagedisplaying scFvs or Fabs that bound to immobilized peptidogenic proteinor starting protein can be identified after panning on immobilizedpeptidogenic protein or starting protein and assessing by ELISA forbinding to immobilized peptidogenic protein or starting protein. Thepeptidogenic protein or starting protein that is immobilized on platesfor these assays can be purified from supernatants of Sf9 cells infectedwith a baculovirus expression construct as described in Moore et al.,Science 285:260-263 or from supernatants from HEK293 cells. Each of theidentified scFvs or Fabs can then be sequenced.

To determine the specificity of each of the unique scFvs or Fabs, aphage ELISA can be performed for each scFvs or Fabs against thepeptidogenic protein or starting protein and control wells. IndividualE. coli colonies containing a phagemid representing one of the uniquescFvs or Fabs can be inoculated into 96-well plates containing 100 μl2TYAG medium per well. Plates are incubated at 37° C. for 4 hours,shaking. M13K07 helper phage is then added to each well to a MOI of 10and the plates are incubated for a further 1 hour at 37° C. The platesare centrifuged in a benchtop centrifuge at 2000 rpm for 10 minutes. Thesupernatant is removed and cell pellets are resuspended in 100 μl 2TYAKand incubated at 30° C. overnight, shaking.

The next day, plates are centrifuged at 2000 rpm for 10 min and the 100μl phage-containing supernatant from each well are carefully transferredinto a fresh 96-well plate. Twenty μl of 6×MPBS is added to each well,and incubated at room temperature for 1 hour to pre-block the phageprior to ELISA.

Flexible 96-well plates (Falcon) are coated overnight at 4° C. with apeptidogenic protein (directly or indirectly, at 1 mg/ml) in PBS, BSA (1g/ml) in PBS, or PBS. After coating, the solutions are removed from thewells, and the plates are blocked for 1 hour at room temperature inMPBS. The plates are washed 3 times with PBS and then 50 μl ofpre-blocked phage is added to each well. The plates are incubated atroom temperature for 1 hour and then washed with 3 changes of PBSTfollowed by 3 changes of PBS. To each well, 50 μl of an anti-geneVIII-HRP conjugate (Pharmacia) at a 1 to 5000 dilution in MPBS is addedand the plates are incubated at room temperature for 1 hour. Each plateis washed three times with PBST followed by three times with PBS. Then50 μl of an HRP-labelled anti-mouse antibody (DAKO EnVision) diluted1/50 in 3% MPBS is added and incubated for 1 hour at room temperature.Each plate is then washed three times with PBST followed by three timeswith PBS. Fifty μl of TMB substrate is then added to each well, andincubated at room temperature for 30 minutes or until color development.The reaction is stopped by the addition of 25 μl of 0.5 M H2SO4. Thesignal generated is measured by reading the absorbance at 450 nm (A450)using a microtiter plate reader (Bio-Rad 3550).

Conversion of scFvs or Fabs to IgG1 format can be performed as follows.The VH domain and the VL domains of scFvs or Fabs that we wish toconvert into IgG molecules can be cloned into vectors containing thenucleotide sequences of the appropriate heavy (human IgG1, IgG2, etc.)or light chain (human kappa or human lambda) constant regions such thata complete heavy or light chain molecule could be expressed from thesevectors when transfected into an appropriate host cell. Further, whencloned heavy and light chains are both expressed in one cell line (fromeither one or two vectors), they can assemble into a complete functionalantibody molecule that is secreted into the cell culture medium. Methodsfor converting scFvs or Fabs into conventional antibody molecules arewell known within the art.

The purification of the IgG from the fermentation broth is performedusing a combination of conventional techniques commonly used forantibody production. Typically the culture harvest is clarified toremove cells and cellular debris prior to starting the purificationscheme. This would normally be achieved by using either centrifugationor filtration of the harvest. Following clarification, the antibodywould typically be captured and significantly purified using affinitychromatography on Protein A Sepharose. The antibody is bound to ProteinA Sepharose at basic pH and, following washing of the matrix, is elutedby a reduction of the pH. Further purification of the antibody is thenachieved by gel filtration. As well as removing components withdifferent molecular weights from the antibody this step can also be usedto buffer exchange into the desired final formulation buffer.

Example 12: Assays Used to Characterize Antibodies and MeasureCross-Reactivity

Antibodies (whether cross-reacting or antibodies raised against thepeptidogenic protein) (including scFvs or Fabs and other moleculescomprising, or alternatively consisting of, antibody fragments orvariants thereof) may be screened in a variety of assays, some of whichare described below to identify those antibodies that bind to thepeptidogenic protein and/or starting protein.

In one particular assay, antibodies (whether cross-reacting orantibodies raised against the peptidogenic protein) that bind to abiotinylated protein (whether the peptidogenic protein and/or startingprotein) can be captured on streptavidin coated magnetic beads. Thisassay may be applied to identify antibodies (whether cross-reacting orantibodies raised against the peptidogenic protein) that neutralizeand/or bind to the peptidogenic protein and/or starting protein.Additionally, antibodies may be assayed in neutralization assaysdescribed herein or otherwise known in the art. For example, where thetarget protein is BlyS, antibodies may be tested for their ability toinhibit the peptidogenic protein and/or starting protein from binding toIM9 cells. In this assay, labeled peptidogenic protein and/or startingprotein (e.g., biotinylated) is incubated with antibodies to allow forthe formation of protein-antibody complexes. Following incubation, analiquot of the protein-antibody sample is added to IM9 cells. Bindingmay be determined using techniques known in the art. For example, thebinding of biotinylated protein (whether the peptidogenic protein and/orstarting protein) to IM9 cells may be detected using a fluorimeterfollowing the addition of streptavidin-delfia. Biotinylated protein, ifit is not bound by antibodies that neutralize the protein, will bind tothe cells and can be detected. Thus, an antibody that decreases theamount of biotinylated-protein that binds to IM9 cells (relative to acontrol sample in which the protein had been preincubated with anirrelevant antibody or no antibody at all) is identified as one thatbinds to and neutralizes the protein.

Other immunoassays which can be used to analyze cross-reactivity and/orcharacterize the antibodies raised against the peptidogenic proteininclude, but are not limited to, competitive and non-competitive assaysystems using techniques such as western blots, radioimmunoassays, ELISA(enzyme linked immunosorbent assay), “sandwich” immunoassays,immunoprecipitation assays, precipitin reactions, gel diffusionprecipitin reactions, immunodiffusion assays, agglutination assays,complement-fixation assays, immunoradiometric assays, fluorescentimmunoassays, and protein A immunoassays, to name but a few. Such assaysare routine and well known in the art (see, e.g., Ausubel et al, eds,1994, Current Protocols in Molecular Biology, Vol. 1, John Wiley & Sons,Inc., New York.

Exemplary immunoassays are described briefly below (but are not intendedby way of limitation) Immunoprecipitation protocols generally compriselysing a population of cells in a lysis buffer such as RIPA buffer (1%NP-40 or Triton X-100, 1% sodium deoxycholate, 0.1% SDS, 0.15 M NaCl,0.01 M sodium phosphate at pH 7.2, 1% Trasylol) supplemented withprotein phosphatase and/or protease inhibitors (e.g., EDTA, PMSF,aprotinin, sodium vanadate), adding the cross-reacting antibody ofinterest to the cell lysate, incubating for a period of time (e.g., 1 to4 hours) at 4° C., adding protein A and/or protein G sepharose beads tothe cell lysate, incubating for about an hour or more at 4° C., washingthe beads in lysis buffer and resuspending the beads in SDS/samplebuffer. The ability of the antibody of interest to immunoprecipitate apeptidogenic protein and/or a starting protein can be assessed by, e.g.,western blot analysis or mass spectrometry. One of skill in the artwould be knowledgeable as to the parameters that can be modified toincrease the binding of the antibody to a peptidogenic protein and/or astarting protein and decrease the background (e.g., pre-clearing thecell lysate with sepharose beads). For further discussion regardingimmunoprecipitation protocols see, e.g., Ausubel et al, eds, 1994,Current Protocols in Molecular Biology, Vol. 1, John Wiley & Sons, Inc.,New York at 10.16.1.

Western blot analysis generally comprises preparing protein samples,electrophoresis of the protein samples in a polyacrylamide gel (e.g.,8%-20% SDS-PAGE depending on the molecular weight of the antigen),transferring the protein sample from the polyacrylamide gel to amembrane such as nitrocellulose, PVDF or nylon, blocking the membrane inblocking solution (e.g., PBS with 3% BSA or non-fat milk), washing themembrane in washing buffer (e.g., PBS-Tween 20), blocking the membranewith primary antibody (the antibody of interest) diluted in blockingbuffer, washing the membrane in washing buffer, blocking the membranewith a secondary antibody (which recognizes the primary antibody, e.g.,an anti-human antibody) conjugated to an enzymatic substrate (e.g.,horseradish peroxidase or alkaline phosphatase) or radioactive molecule(e.g., 32P or 1211) diluted in blocking buffer, washing the membrane inwash buffer, and detecting the presence of the antigen. One of skill inthe art would be knowledgeable as to the parameters that can be modifiedto increase the signal detected and to reduce the background noise. Forfurther discussion regarding western blot protocols see, e.g., Ausubelet al, eds, 1994, Current Protocols in Molecular Biology, Vol. 1, JohnWiley & Sons, Inc., New York at 10.8.1.

In a further example, ELISAs comprise preparing peptidogenic proteinand/or a starting protein, coating the well of a 96-well microtiterplate (directly or indirectly) with the peptidogenic protein and/or astarting protein, washing away the peptidogenic protein and/or astarting protein that did not bind the wells, adding the antibody ofinterest conjugated to a detectable compound such as an enzymaticsubstrate (e.g., horseradish peroxidase or alkaline phosphatase) to thewells and incubating for a period of time, washing away unboundantibodies or non-specifically bound antibodies, and detecting thepresence of the antibodies specifically bound to the peptidogenicprotein and/or a starting protein coating the well. In ELISAs theantibody of interest does not have to be conjugated to a detectablecompound; instead, a second antibody (which recognizes the antibody ofinterest) conjugated to a detectable compound may be added to the well.

Further, instead of coating the well with the antigen, the antibody maybe coated to the well. In this case, the detectable molecule could bethe peptidogenic protein and/or a starting protein conjugated to adetectable compound such as an enzymatic substrate (e.g., horseradishperoxidase or alkaline phosphatase). One of skill in the art would beknowledgeable as to the parameters that can be modified to increase thesignal detected as well as other variations of ELISAs known in the art.For further discussion regarding ELISAs see, e.g., Ausubel et al, eds,1994, Current Protocols in Molecular Biology, Vol. 1, John Wiley & Sons,Inc., New York at 11.2.1. The binding affinity of an antibody to apeptidogenic protein and/or a starting protein and the off-rate of anantibody-protein interaction can be determined by competitive bindingassays. One example of a competitive binding assay is a radioimmunoassaycomprising the incubation of labeled peptidogenic protein and/or astarting protein (e.g., 3H or 1251) with the antibody of interest in thepresence of increasing amounts of unlabeled peptidogenic protein and/ora starting protein, and the detection of the antibody bound to thelabeled peptidogenic protein and/or a starting protein. The affinity ofthe antibody of the present invention for a peptidogenic protein and/orthe starting protein and the binding off-rates can be determined fromthe data by Scatchard plot analysis. Competition with a second antibodycan also be determined using radioimmunoassays. In this case, apeptidogenic protein and/or starting protein is incubated with anantibody of interest conjugated to a labeled compound (e.g., 3H or 1251)in the presence of increasing amounts of an unlabeled secondanti-peptidogenic protein antibody.

In a preferred embodiment, BIAcore kinetic analysis can be used todetermine the binding on and off rates of antibodies to peptidogenicprotein and/or starting protein. BIAcore kinetic analysis comprisesanalyzing the binding and dissociation of peptidogenic protein and/orstarting protein from chips with immobilized antibodies on theirsurface.

Example 13: Vaccination

Further, a mixture of peptidogenic proteins as described herein can beused as a vaccine. For example a concentration of 320 ug/mL inphosphate-buffered saline (PBS, 155 mM NaCl, 1 mM KH2PO4, 3 mM Na2HPO3)of the peptidogenic proteins are aseptically emulsified with an equalvolume of Montanide ISA 51 to give a final vaccine concentration of 160ug/mL. The emulsion is achieved by homogenizing the mixture in a volumeof 200 mL in a 400-mL vessel at room temperature for 6 min at 6000 rpmusing an Omni Mixer-ES homogenizer (Omni International, Warren-ton, VA).Each vaccine undergoes comprehensive quality control analyses to ensuregeneral safety, purity, identity, integrity, and uniform water-in-oildroplet size. Stability of vaccines stored at 2-8° C. is evaluatedregularly using mouse immunogenicity tests and physical and biochemicalassays to verify the vaccine safety, potency, uniformity, purity, andintegrity until 4-10 months after the termination of the humanimmunizations. The 160 ug/mL peptidogenic protein vaccines are dilutedwith the PBS/ISA 51 (the adjuvant control vaccine) to the final doseforms of 10 ug/mL or 40 ug/mL prior to immunizations. As a result ofdifferent degrees of dilution, these vaccines contained two differentratios of vaccine-containing vs. vaccine-free water droplets, namelyratios of 1:15 and 1:3 for the 10 ug/mL and 40 ug/mL formulations,respectively. The test and control vaccines may be highly viscous andrequire vortexing prior to and after manipulation to ensure homogeneity.The vaccine can be administered intramuscularly by needle and syringe.Vaccine-induced T-cell responses are further evaluated by means of aqualified intracellular cytokine staining assay. Peripheral-bloodmononuclear cells are quantified to determine the proportion of totaland memory CD4 and CD8 T cells producing interleukin-2, interferon-γ, ortumor necrosis factor (TNF).

Polynucleotides encoding a mixture of peptidogenic proteins can also beused as a vaccine by administering to a patient the polynucleotidedescribed herein.

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The invention claimed is:
 1. A method of generating an immune responsein an animal wherein said method comprises: a. introducing a mixture ofat least two different peptidogenic proteins derived from a startingprotein, wherein each of the peptidogenic proteins has alteredconformational dynamics as compared to the starting protein, whereineach of the peptidogenic proteins is similar in conformation to thestarting protein, and wherein each of the peptidogenic proteinscomprises replacement of at least one non-surface amino acid residue inthe starting protein with a different amino acid residue to an animal;and b. generating an immune response in the animal.
 2. The method ofclaim 1, wherein the conformational dynamics are altered by: a.examining the 3-D structure of the starting protein, identifyingnon-surface amino acid residues of the starting protein and replacing atleast one non-surface amino acid residue in the starting protein togenerate the peptidogenic proteins; or b. examining a model of the 3-Dstructure of the starting protein, identifying non-surface amino acidresidues of the starting protein and replacing at least one non-surfaceamino acid residue in the starting protein to generate the peptidogenicproteins; or c. comparing the pattern of conserved amino acid homologyacross proteins orthologous to the starting protein from differentspecies to identify non-surface amino acid residues of the startingprotein and replacing at least one non-surface amino acid residue in thestarting protein to generate the peptidogenic proteins; or d. replacingat least one non-surface amino acid residue of the starting protein togenerate the peptidogenic proteins; or e. replacing at least onenon-surface amino acid residue with a smaller amino acid residue; or f.replacing at least one non-surface amino acid residue with an alanine orglycine; or g. eliminating at least one disulfide bond in the startingprotein.
 3. The method of claim 1, wherein at least 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acids arereplaced in the starting protein.
 4. The method of claim 1, wherein theconformational dynamics of the starting protein are altered byreplacing: a. at least one non-surface threonine with a valine, alanine,glycine or serine; or b. at least one non-surface cysteine with alanine,valine, glycine, serine or threonine; or c. at least one non-surfacevaline with alanine, glycine, leucine or isoleucine; or d. at least onenon-surface leucine with alanine, valine, glycine, or isoleucine; or e.at least one non-surface isoleucine with alanine, valine, leucine, orglycine; or f. at least one non-surface proline with methionine,alanine, valine, leucine, isoleucine, or glycine; or g. at least onenon-surface methionine with alanine, valine, leucine, isoleucine, orglycine; or h. at least one non-surface phenylalanine with tyrosine,methionine, histidine, alanine, valine, leucine, isoleucine, or glycine;or i. at least one non-surface tyrosine with phenylalanine, methionine,histidine, alanine, valine, leucine, isoleucine, or glycine; or j. atleast one non-surface tryptophan with tyrosine, phenylalanine,methionine, histidine, alanine, valine, leucine, isoleucine, or glycine;or k. at least one non-surface aspartic acid with glutamic acid,glutamine, asparagine, glycine, serine, threonine, alanine, valine,leucine, or isoleucine; or l. at least one non-surface asparagine withglycine, serine, threonine, alanine, valine, leucine, isoleucine,glutamine, glutamic acid, or aspartic acid; or m. at least onenon-surface glutamic acid with aspartic acid, asparagine, glutamine,glycine, serine, threonine, alanine, valine, leucine, or isoleucine; orn. at least one non-surface glutamine with glutamic acid, aspartic acid,asparagine, glutamine, glycine, serine, threonine, alanine, valine,leucine, or isoleucine; or o. at least one non-surface lysine witharginine, histidine, glycine, serine, threonine, alanine, valine,methionine, leucine, or isoleucine; or p. at least one non-surfacearginine with lysine, histidine, glycine, serine, threonine, alanine,valine, methionine, leucine, or isoleucine; or q. at least onenon-surface histidine with phenylalanine, tyrosine, lysine, arginine,glycine, serine, threonine, alanine, valine, glutamine, asparagine,leucine, methionine or isoleucine; or r. at least one non-surfacealanine with a glycine or proline; or s. at least one non-surfaceglycine with an alanine or proline; or t. at least one non-surfaceserine with an alanine or glycine; or u. at least one non-surfaceresidue with a non-natural amino acid; or v. a combination of any of theabove replacements.
 5. The method of claim 1, wherein the alteredconformational dynamics of the peptidogenic proteins is measured by: a.a change in melting temperature as compared to the starting protein; orb. a change in Gibbs free energy of stabilization or proteolyticsensitivity assay; or c. a change in Gibbs free energy, wherein thechange in Gibbs free energy of stabilization is measured by denaturantmodulated equilibrium unfolding, wherein the denaturant is urea orguanidinium hydrochloride.
 6. The method of claim 1, wherein similarityin conformation to the starting protein is measured by: binding of across-reacting antibody to both the peptidogenic proteins and thestarting protein; optionally wherein (a) binding of the cross-reactiveantibody is measured by an immunoprecipitation assay, surface plasmonresonance, isothermal titration calorimetry, oblique-incidencereflective difference (OI-RD), western blots, radioimmunoassays, ELISA(enzyme linked immunosorbent assay), “sandwich” immunoassays, geldiffusion precipitin reactions, immunodiffusion assays, agglutinationassays, complement-fixation assays, immunoradiometric assays,fluorescent immunoassays, and/or protein A immunoassays; and/or (b) thecross-reacting antibody has a dissociation constant (KD) to the startingprotein and the peptidogenic proteins of less than or equal to 10⁻⁹M;and/or (c) the cross-reacting antibody has a dissociation constant (KD)to the starting protein and the peptidogenic proteins of less than orequal to 10⁻⁸M, less than or equal to 10⁻⁷M, or less than or equal to10⁻⁶M.
 7. The method of claim 1, wherein the starting protein isselected from: a. an envelope glycoprotein of the human immunodeficiencyvirus (HIV), HIV gp120, HIV gp41, HIV gp160, an ebola antigen, a viralantigen, a bacterial antigen, a parasite antigen, an allergen, a venom,a toxin, a tumor-associated antigen, a transmembrane domain protein, aG-protein coupled receptor, an ion channel, a hepatitis C virus antigen,a hepatitis B virus antigen, a MERS-CoV antigen, a Zika virus antigen,an influenza virus antigen, a malaria antigen; and/or b. any one of themalaria antigens selected from MAL13P1.225, PF13 0203, PF11 0164,PFLO375W, PFI1270W, PF10 0104, PF13 0128, PF11 0058, PFA0490W, PF070087, PFB0570W, PF13 0180, PF11 0065, PF14 0678, PF13 0125, PF13 0141,PF14 0117, PF11 0098, PF14 0660, PFD0240C, PFE0080C, PFA0660W, PF110352, PF11 0055, PFB0475C, PF11 0302, PFA0210C, PF07 0089, PF14 0060,MAL8P1.17, MAL7P1.77, PF11 0099, PF07 0068, PF13 0201, PF07 0094, PF070006, PFLO770W, PFI1645C, PF14 0166, PFE0815W, PF11 0174, PFE0475W, PF110074, PFL1385C, PF14 0102, PF11 0212, PF07 0129, PFL2570W, PFL1070C,PFB0695C, PF11 0175, MAL13P1.22, PFLO035C, PFI0685W, PFD0425W, PF140293, PF14 0344, PFLO560C, PF07 0035, PFL1675C, PFC0435W, PFI1445W, PF130354, PFC0110W, PFC0120W, PF08 0078, PF14 0614, PF14 0051, PF11 0076,MAL13P1.262, PFC0640W, PFL2520W, PFCO282W, PF08 0004, PF11 0224, PF130272, MAL13P1.171, PFE1340W, PF14 0369, PF14 0178, PFLO870W, PFCO210C,PFI0500W, PF11 0069, PFD0355C, PFI0880C, PF11 0251, PFC0065C, PFC0925W,MAL13P1.121, PF13 0133, PFL2015W, PFD0440W, PFC0330W, PFD0430C, PF140462, PF07 0100, MAL7P1.23, PFL1835W, PF07 0047, PF14 0250, PFE0905W,PFA0180W, PFL1210W, PF14 0363, PFB0400W, PFI0920C, PF14 0094, PFA0125C,PF10 0372, PFL2315C, MAL13P1.271, MAL7P1.31, PF10 0317, PF07 0070,MAL7P1.64, PFI0935W, PFA0160C, PFB0465C, PF10 0208, PFB0760W,MAL13P1.206, PF14 0541, PFLO790W, PFL2410W, PF14 0440, PF11 0333, PF100242, PFC0590C, PF14 0342, MAL7P1.92, PF14 0593, MAL13P1.49,MAL13P1.172, PF08 0006, PFD1035W, PF11 0052, MAL13P1.79, PF10 0295,PFL1745C, PF14 0677, PFLO600W, PF08 0108, PF08 0081, PF14 0620,PFE0710W, PF11 0270, MAL7P1.149, PFC0810C, PF14 0249, PF13 0116,MAL13P1.60, PF11 0246, PFL2505C, PFB0405W, PF11 0256, PF08 0047,PFC0835C, PFI0605C, PF10 0127, PF11 0344, PF10 0130, PFL2395C, PF080008, PF14 0201, PFI1475W, PF13 0182, PF14 0495, or PF13 0277; and/or c.any one of the Targets selected from A4GCL9, A8T655, B2R7F8, B4DEZ9,B4DTR1, D4HNR6, D5RWT1, F8WCM5, G8EJ09, I6YE93, K9N5Q8, 000141, 000189,000206, 000220, 000253, 000294, 000300, 000522, 000585, 000754, 014522,014763, 014773, 014788, 014793, 014807, 014836, 014896, 014931, 014936,014976, 014994, 015020, 015118, 015230, 015305, 015357, 015372, 015394,015455, 015520, 043155, 043291, 043323, 043424, 043557, 043570, 043707,043854, 043897, 043933, 060229, 060494, 060565, 060602, 060706, 060840,060882, 075197, 075367, 075369, 075436, 075581, 075665, 075695, 075712,075874, 075888, 075923, 075970, 076041, 076090, 094804, 095150, 095256,095342, 095407, 095445, 095452, 095633, 095760, 095967, P00167, P00338,P00387, P00403, P00439, P00441, P00451, P00488, P00492, P00519, P00533,P00568, P00734, P00740, P00742, P00746, P00747, P00748, P00751, P00797,P00918, P00966, P00995, P01008, P01009, P01019, P01024, P01031, P01032,P01034, P01111, P01127, P01130, P01137, P01138, P01185, P01241, P01308,P01344, P01374, P01375, P01579, P01583, P01584, P01588, P01589, P01730,P01854, P01889, P01903, P01906, P01909, P01911, P01912, P01920, P02452,P02458, P02461, P02462, P02489, P02647, P02649, P02671, P02675, P02679,P02708, P02730, P02760, P02766, P02768, P02792, P03147, P03372, P03420,P03441, P03446, P03448, P03456, P03457, P03471, P03472, P03474, P03476,P03477, P03478, P03886, P03950, P03951, P04040, P04049, P04062, P04070,P04080, P04155, P04156, P04179, P04180, P04233, P04234, P04275, P04424,P04440, P04578, P04626, P04629, P04661, P04792, P04839, P05019, P05062,P05067, P05089, P05091, P05106, P05107, P05112, P05113, P05121, P05129,P05155, P05156, P05186, P05231, P05386, P05540, P05556, P05961, P05997,P06127, P06213, P06239, P06280, P06340, P06396, P06681, P06684, P06737,P06744, P06804, P06865, P07204, P07225, P07288, P07339, P07477, P07585,P07602, P07686, P07911, P07949, P07954, P08034, P08100, P08118, P08133,P08183, P08235, P08236, P08237, P08246, P08253, P08326, P08473, P08514,P08519, P08567, P08572, P08575, P08581, P08603, P08617, P08708, P08709,P08887, P09417, P09467, P09603, P09619, P09668, P09936, P09960, POCOL4,POCOLS, PODJI8, PODJI9, P10071, P10321, P10448, P10619, P10721, P10809,P10828, P10912, P11021, P11132, P11166, P11168, P11177, P11215, P11217,P11224, P11230, P11233, P11310, P11362, P11413, P11532, P11586, P11597,P11836, P12023, P12111, P12259, P12318, P12643, P12644, P12821, P12830,P12955, P13103, P13224, P13500, P13569, P13612, P13637, P13716, P13726,P13747, P13765, P13804, P13807, P14138, P14174, P14207, P14210, P14222,P14416, P14672, P14770, P14778, P14780, P14784, P14867, P14921, P14923,P15018, P15259, P15260, P15289, P15291, P15313, P15328, P15391, P15509,P15529, P15692, P15814, P15848, P15907, P15924, P15941, P16109, P16144,P16154, P16278, P16401, P16410, P16422, P16442, P16473, P16871, P16930,P17050, P17174, P17693, P17787, P17858, P17900, P17927, P17948, P18074,P18177, P18206, P18510, P19079, P19235, P19256, P19320, P19438, P19694,P19838, P19876, P20023, P20036, P20138, P20151, P20273, P20701, P20702,P20749, P20807, P20849, P20929, P20933, P21333, P21359, P21439, P21580,P21583, P21709, P21781, P21802, P21817, P21860, P21912, P22105, P22223,P22301, P22362, P22413, P22460, P22735, P22748, P23284, P23415, P23468,P23510, P23560, P23945, P23975, P24723, P24855, P25024, P25025, P25054,P25189, P25445, P26010, P26136, P26927, P27169, P27487, P27909, P27930,P27958, P28062, P28068, P28472, P28482, P28799, P28907, P28908, P29033,P29120, P29216, P29320, P29323, P29400, P29459, P29460, P29590, P29597,P29965, P30044, P30203, P30301, P30460, P30530, P30556, P31371, P31785,P31994, P31995, P31997, P32297, P32754, P33681, P33795, P34059, P34130,P35221, P35222, P35225, P35442, P35462, P35475, P35555, P35579, P35609,P35625, P35670, P35749, P35754, P35968, P35991, P36222, P36871, P36888,P36894, P36896, P36897, P36915, P36941, P36955, P37023, P37173, P38117,P39019, P39023, P39060, P39905, P40225, P40238, P40259, P40394, P41159,P41180, P41181, P41250, P42081, P42261, P42263, P42336, P42568, P42658,P42702, P42768, P43026, P43034, P43235, P43258, P43259, P43260, P43681,P44815, P45381, P45954, P46094, P46379, P46459, P46531, P46783, P46934,P46952, P47756, P48023, P48061, P48167, P48436, P48544, P48643, P49257,P49419, P49588, P49683, P49747, P49768, P49789, P49810, P50440, P50454,P50570, P50897, P50993, P51149, P51159, P51532, P51570, P51608, P51648,P51681, P51688, P51690, P51693, P51787, P51800, P51812, P51813, P52788,P52803, P53004, P53420, P53634, P54098, P54577, P54764, P54802, P54803,P54819, P55008, P55072, P55075, P55268, P55286, P55291, P55789, P56537,P57075, P57735, P58335, P59594, P60033, P60484, P60568, P60900, P60953,P61457, P61626, P61769, P61812, P61916, P62070, P62081, P62736, P62854,P62913, P63092, P63252, P67870, P68032, P68036, P68133, P68871, P69905,P78324, P78363, P78380, P78504, P78509, P78545, P80098, P82279, P84022,P98082, P98160, P98161, Q00653, Q00973, Q01484, Q01955, Q01968, Q02223,Q02297, Q02388, Q02413, Q02487, Q03154, Q03403, Q03426, Q03591, Q04446,Q04609, Q04656, Q04721, Q04771, Q04844, Q05397, Q05495, Q05586, Q06124,Q06187, Q07001, Q07108, Q07599, Q07954, Q07FI5, Q08048, Q08334, Q08345,Q08881, Q09428, Q09470, Q0A2R1, Q0A448, Q0ED31, Q0Z7S6, Q0ZME7, Q0ZNA6,Q12791, Q12809, Q12879, Q12965, Q13002, Q13009, Q13018, Q13093, Q13126,Q13224, Q13231, Q13253, Q13410, Q13421, Q13424, Q13478, Q13496, Q13501,Q13563, Q13614, Q13620, Q13651, Q13698, Q13753, Q13822, Q13835, Q13873,Q13936, Q14019, Q14103, Q14108, Q14114, Q14117, Q14126, Q14204, Q14315,Q14376, Q14563, Q14571, Q14573, Q14654, Q14833, Q14956, Q14974, Q15027,Q15046, Q15109, Q15116, Q15149, Q15223, Q15262, Q15303, Q15465, Q15582,Q15746, Q15822, Q15831, Q15833, Q15848, Q16288, Q16348, Q16515, Q16552,Q16566, Q16787, Q16827, Q189K3, Q189K5, Q18PE1, Q1HLC5, Q1HP67, Q1PHM6,Q28090, Q289M7, Q29974, Q29980, Q29983, Q2M1P5, Q2N0S5, Q2N0S6, Q30154,Q30201, Q32ZE1, Q3T906, Q3UV74, Q3ZC95, Q3ZLH8, Q46342, Q49DS8, Q4KMG0,Q53SF7, Q59FL8, Q59H50, Q5D862, Q5JWF2, Q5T2T1, Q5VV43, Q5VWQ8, Q5VYX0,Q67333, Q69994, Q6DQ33, Q6IQ55, Q6KF10, Q6PHW0, Q6Q1S2, Q6TXC0, Q6VMK1,Q6XV28, Q71U36, Q75760, Q7L0Q8, Q7LG56, Q7Z6G8, Q7Z6Z7, Q82559, Q84850,Q86UR5, Q86UX7, Q8IU80, Q8IWT1, Q8IZI9, Q8IZJ0, Q8IZP0, Q8IZU9, Q8J581,Q8JDI3, Q8N0W4, Q8N157, Q8N1C3, Q8N5C8, Q8N608, Q8NBP7, Q8NCM8, Q8NFY4,Q8NG31, Q8Q7Z9, Q8TDA6, Q8TDX5, Q8TEW8, Q8TF72, Q8WWA0, Q8WX93, Q8WXD0,Q8WXH0, Q8WXI7, Q91MA7, Q92185, Q92542, Q92597, Q92692, Q92736, Q92743,Q92765, Q92766, Q92796, Q92834, Q92838, Q92887, Q92956, Q93052, Q93099,Q969J5, Q96B97, Q96F46, Q96FE5, Q96HC4, Q96J02, Q96J92, Q96MS0, Q96P20,Q96PD4, Q96PX8, Q96QZ7, Q993A8, Q99466, Q99497, Q99877, Q99972, Q99985,Q9BQB4, Q9BUL8, Q9BWV1, Q9BXJ0, Q9BXM0, Q9BXR6, Q9BZ11, Q9C000, Q9D1H1,Q9DBR4, Q9EQF4, Q9GZV9, Q9H0F7, Q9H0U3, Q9H221, Q9H222, Q9H251, Q9H3Z4,Q9H4F8, Q9H6X2, Q9HB21, Q9HBA0, Q9HBE4, Q9HCE7, Q9HCK4, Q9HD26, Q9HDB5,Q9IGQ6, Q9J3E7, Q9NPF7, Q9NQ25, Q9NQ38, Q9NQC7, Q9NS40, Q9NVA2, Q9NVD7,Q9NY72, Q9NZ08, Q9NZN1, Q9NZQ7, Q9NZV8, Q9P1W8, Q9UBP0, Q9UBQ7, Q9UBV7,Q9UBX5, Q9UGJ0, Q9UGM3, Q9UHF4, Q9UHG0, Q9UHN1, Q9UHP7, Q9UIR5, Q9UKL4,Q9UKM7, Q9UKQ2, Q9ULV1, Q9ULV5, Q9UM47, Q9UM54, Q9UNA1, Q9UNG2, Q9UPW8,Q9W7Y7, Q9WFX3, Q9WMX2, Q9Y275, Q9Y281, Q9Y2Q5, Q9Y496, Q9Y4CO, Q9Y4J8,Q9Y5K2, Q9Y5K6, Q9Y6D5, Q9Y6N8, or Q9Y6Q6; and/or d. a tumor associatedantigen selected from MAGE-A1, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A5,MAGE-A6, MAGE-A7, MAGE-A8, MAGE-A9, MAGE-A10, MAGE-A1 1, MAGE-A12,GAGE-I, GAGE-2, GAGE-3, GAGE-4, GAGE-5, GAGE-6, GAGE-7, GAGE-8, BAGE-I,RAGE-1, LB33/MUM-1, PRAME, NAG, MAGE-Xp2 (MAGE-B2), MAGE-Xp3 (MAGE-B3),MAGE-Xp4 (MAGE-B4), MAGE-C1/CT7, MAGE-C2, NY-ESO-I, LAGE-I, SSX-I,SSX-2(HOM-MEL-40), SSX-3, SSX-4, SSX-5, SCP-I and XAGE, melanocytedifferentiation antigens, p53, ras, CEA, MUC1, PMSA, PSA, tyrosinase,Melan-A, MART-1, gp100, gp75, alpha-actinin-4, Bcr-Abl fusion protein,Casp-8, beta-catenin, cdc27, cdk4, cdkn2a, coa-1, dek-can fusionprotein, EF2, ETV6-AML1 fusion protein, LDLR-fucosyltransferaseAS fusionprotein, HLA-A2, HLA-All, hsp70-2, KIAAO205, Mart2, Mum-2, and 3,neo-PAP, myosin class I, OS-9, pml-RAR alpha fusion protein, PTPRK,K-ras, N-ras, Triosephosphate isomerase, GnTV, Herv-K-mel, NA-88, SP17,and TRP2-Int2, (MART-I), E2A-PRL, H4-RET, IGH-IGK, MYL-RAR, Epstein Barrvirus antigens, EBNA, human papillomavirus (HPV) antigens E6 and E7,TSP-180, MAGE-4, MAGE-5, MAGE-6, p185erbB2, p180erbB-3, c-met, nm-23H1,PSA, TAG-72-4, CA 19-9, CA 72-4, CAM 17.1, NuMa, K-ras,alpha-fetoprotein, 13HCG, BCA225, BTAA, CA 125, CA 15-3 (CA 27.29\BCAA),CA 195, CA 242, CA-50, CAM43, CD68\KP1, CO-029, FGF-5, G250, Ga733(EpCAM), HTgp-175, M344, MA-50, MG7-Ag, MOV18, NB\170K, NY-CO-1, RCAS1,SDCCAG16, TA-90 (Mac-2 binding protein\cyclophilin C-associatedprotein), TAAL6, TAG72, TLP, TPS, tyrosinase related proteins, TRP-1,TRP-2, or cytomegalovirus phosphoprotein 65 (pp65).
 8. The method ofclaim 1, wherein the mixture of peptidogenic proteins is introduced intothe animal by: a. administering the mixture of peptidogenic proteins tothe animal; b. administering a mixture of polynucleotides encoding themixture of peptidogenic proteins to the animal; and/or c. administeringto the animal antigen presenting cells transfected with the mixture ofpolynucleotides and/or placed in contact with the mixture ofpeptidogenic proteins.
 9. The method of claim 1, wherein thepeptidogenic proteins are derived: a. from the same starting protein; orb. from multiple starting proteins; or c. from multiple related startingproteins.
 10. The method of claim 8, wherein the mixture of peptidogenicproteins is introduced into the animal by administering a mixture ofpolynucleotides encoding the mixture of peptidogenic proteins to theanimal, and wherein the polynucleotides: a. are synthesized in vitro; orb. comprise DNA; or c. comprise in vitro transcribed (IVT) mRNA; or d.comprise IVT mRNA comprising a poly(A) tail; or e. comprise IVT mRNAcomprising a 5′ Cap, optionally wherein the polynucleotides are: 1) notassociated with any targeting components; or 2) are associated with atargeting component capable of targeting the polynucleotides to a cellor an organ; or 3) are associated with a targeting component capable oftargeting the polynucleotides to a cell or an organ, wherein thetargeting component is a vector.
 11. The method of claim 1 wherein theanimal is a mammal, a human, mouse, rabbit, llama, or a cow.
 12. Themethod of claim 8, wherein the animal is injected with thepolynucleotides, wherein the polynucleotides are: a. injected directlyinto the muscle of the animal; and/or b. injected into the animal onmultiple occasions.
 13. The method of claim 1, wherein the immuneresponse generates antibodies.
 14. The method of claim 13, wherein themethod further comprises isolating the antibodies.
 15. The method ofclaim 14, wherein the antibodies are fully human antibodies, chimericantibodies, humanized antibodies, monoclonal antibodies, and/orpolyclonal antibodies.
 16. The method of claim 13, wherein the methodfurther comprises affinity maturing the antibodies, wherein the affinitymaturation occurs by: a. phage display, yeast display or ribosomedisplay; or b. a panning technique.
 17. The method of claim 1, whereinthe mixture of peptidogenic proteins further comprises the startingprotein.
 18. The method of claim 1, wherein each of the peptidogenicproteins has increased conformational dynamics as compared to thestarting protein.